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Zugaro, L. M., G. E. Reid, et al. (1998). "Characterization of rat brain stathmin isoforms by two-dimensional gel electrophoresis-matrix assisted laser desorption/ionization and electrospray ionization-ion trap mass spectrometry." Electrophoresis 19(5): 867-76.
Stathmin is a regulatory phosphoprotein that is a target for both cell cycle and cell surface receptor-regulated phosphorylation events. There are at least 14 isoforms of stathmin that migrate on two-dimensional electrophoresis (2-DE): two unphosphorylated, and 12 increasingly phosphorylated proteins. Following extracellular stimuli, stathmin is phosphorylated on four serines (Ser16, Ser25, Ser38, and Ser63) by several kinases, such as mitogen-activated protein (MAP), cdc2 kinase, protein kinase A, and Ca2+/calmodulin-dependent kinase-Gr. While all forms of stathmin are derived from the same protein encoded by a single mRNA, the precise nature of the post-translational modifications has not been clear. In this study we have characterized three rat brain stathmin isoforms, #1, #3 and #4, which electrophorese on 2-DE with apparent molecular weight (Mr)/isoelectric point (pI) values of 15,500/6.2, 15,000/6.1, and 15,000/6.0, respectively. The phosphorylation status of these isoforms was determined using a combination of peptide mapping, matrix-assisted laser desorption/ionization mass spectrometry and electrospray-ionization ion trap mass spectrometry. Stathmin isoform #1 was not phosphorylated, stathmin isoform #3 was phosphorylated on Ser38 only, and stathmin isoform #4 was phosphorylated on Ser38; however, the phosphorylation status of Ser63 could not be determined. In addition, three proteins which electrophorese near stathmin were identified in order to more accurately define the Mr/pI locus of this region of the 2-DE gel map. These include: phosphatidyl ethanolamine binding protein (Mr approximately 18,000/pI 6.0), synuclein forms 2 and 3 (Mr approximately 14,000/pI 5.4), and synuclein form 2 (Mr approximately 15,000/pI 5.0).

Zareparsi, S., J. Kaye, et al. (1998). "Analysis of the alpha-synuclein G209A mutation in familial Parkinson's disease." Lancet 351(9095): 37-8.

Warner, T. T. and A. H. Schapira (1998). "The role of the alpha-synuclein gene mutation in patients with sporadic Parkinson's disease in the United Kingdom." J Neurol Neurosurg Psychiatry 65(3): 378-9.
Parkinson's disease is a common neurodegenerative disorder of unknown aetiology. A pathogenic point mutation within the a-synuclein gene has recently been identified in one Italian-American kindred and three families of Greek origin with parkinsonism. DNA from 70 patients with Parkinson's disease was screened for this G209A mutation. No samples were positive for the mutation, suggesting that it is not relevant for most patients with sporadic idiopathic Parkinson's disease.

Wang, W. W., M. Khajavi, et al. (1998). "The G209A mutation in the alpha-synuclein gene is not detected in familial cases of Parkinson disease in non-Greek and/or Italian populations." Arch Neurol 55(12): 1521-3.
OBJECTIVE: To determine whether the G-to-A substitution at nucleotide 209 (G209A) mutation in the alpha-synuclein gene is responsible for familial Parkinson disease (PD) in the US population. DESIGN: Polymerase chain reaction-based DNA analysis of consecutive patients with PD and family history of PD. SETTING: A university-affiliated movement disorder clinic and a Veterans Affairs clinical research laboratory. PATIENTS: Forty-four patients with PD and family history of PD and 29 patients with sporadic PD, all with no known Greek and/or Italian background. RESULTS: None of the DNA samples showed the G209A mutation. CONCLUSION: The G209A mutation is rare in US patients with familial PD.

Wakabayashi, K., S. Hayashi, et al. (1998). "Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy." Acta Neuropathol (Berl) 96(5): 445-52.
Recently, we have shown that the precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP), also known as alpha-synuclein, is a major component of Lewy bodies (LBs) as well as neuronal and glial cytoplasmic inclusions in multiple system atrophy (MSA). To elucidate whether the accumulation of NACP is specific to LB disease and MSA, we further studied 83 autopsied cases with various neurological disorders, using anti-NACP antibodies. In LB disease, NACP immunoreactivity was present in all of the LBs and Lewy neurites in both the central and peripheral nervous systems, the pale bodies in the substantia nigra, and dystrophic neurites in the hippocampal CA2/3 region. Immunoelectron microscopy revealed that the reaction product was localized within filamentous structures and associated granular structures. In MSA, NACP immunoreactivity was found in the intracytoplasmic inclusions of both neuronal and oligodendroglial cells, neuronal intranuclear inclusions, and swollen neuronal processes. No NACP immunoreactivity was found in a variety of other neuronal or glial inclusions in other disorders, including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, motor neuron disease and triplet-repeat diseases. These findings strongly suggest that the accumulation of NACP is a cytopathological feature common to LB disease and MSA.

Wakabayashi, K., M. Yoshimoto, et al. (1998). "Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy." Neurosci Lett 249(2-3): 180-2.
Lewy bodies in Parkinson' s disease (PD) are strongly immunoreactive with antibodies against alpha-synuclein, which is mutated in some familial cases of the disease. We carried out immunohistochemical examinations of the brains of multiple system atrophy (MSA) patients using anti-alpha-synuclein antibodies. Strong alpha-synuclein immunoreactivity was found in glial cytoplasmic inclusions (GCIs), which are of oligodendroglial origin and occur exclusively in MSA. Alpha-synuclein-immunoreactive neuronal cytoplasmic inclusions (NCIs) were also found occasionally in the substantia nigra, pontine and inferior olivary nuclei, and dentate fascia. These findings indicate that alpha-synuclein is also a major component of GCIs and NCIs in MSA and strongly suggest that alpha-synuclein aggregation is a common process in certain neurodegenerative diseases, including PD and MSA.

Veldman, B. A., A. M. Wijn, et al. (1998). "Genetic and environmental risk factors in Parkinson's disease." Clin Neurol Neurosurg 100(1): 15-26.
Parkinson's disease (PD) is a multifactorial disorder, caused by a combination of age, genetics and environmental factors. Nigral cells are susceptible to multiple causes of derangement of normal cell function, all of which may contribute to the same Parkinson phenotype. Autosomal dominant alpha-synuclein-gene PD represents one of the pure genetic forms, whereas cases of sporadic PD probably depend more on age and environmental factors, MPTP-Parkinsonism being the purest example of an environmentally caused Parkinson phenotype. This review suggests that pesticides-herbicides, smoking and head trauma probably represent the most eligible candidates for environmental factors involved in provoking PD or influencing its natural course.

Vaughan, J., A. Durr, et al. (1998). "The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: a study of 230 European cases. European Consortium on Genetic Susceptibility in Parkinson's Disease." Ann Neurol 44(2): 270-3.
We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.

Vaughan, J. R., M. J. Farrer, et al. (1998). "Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)." Hum Mol Genet 7(4): 751-3.
A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha-synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.

Tu, P. H., J. E. Galvin, et al. (1998). "Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein." Ann Neurol 44(3): 415-22.
Recently, alpha-synuclein was shown to be a structural component of the filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs (DLB) as well as the LB variant of Alzheimer's disease, and this suggests that alpha-synuclein could play a mechanistic role in the pathogenesis of these disorders. To determine whether alpha-synuclein is a building block of inclusions in other neurodegenerative movement disorders, we examined brains from patients with multiple system atrophy (MSA) and detected alpha-synuclein, but not beta- or gamma-synuclein, in glial cytoplasmic inclusions (GCIs) throughout the MSA brain. In MSA white matter, alpha-synuclein-positive GCIs were restricted to oligodendrocytes, and alpha-synuclein was localized to the filaments in GCIs by immunoelectron microscopy. Finally, we demonstrated that insoluble alpha-synuclein accumulated selectively in MSA white matter with alpha-synuclein-positive GCIs. Taken together with evidence that LBs contain insoluble alpha-synuclein, our data suggest that a reduction in the solubility of alpha-synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells as well as neurons in neurodegenerative disorders with different phenotypes.

Trojanowski, J. Q., M. Goedert, et al. (1998). "Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia." Cell Death Differ 5(10): 832-7.
The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB). Aggregated neurofilament subunits and alpha-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD. Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD. Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils.

Trojanowski, J. Q. and V. M. Lee (1998). "Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia." Arch Neurol 55(2): 151-2.

Takeda, A., M. Hashimoto, et al. (1998). "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment." Lab Invest 78(9): 1169-77.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.

Takeda, A., M. Mallory, et al. (1998). "Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders." Am J Pathol 152(2): 367-72.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as a-synuclein) is a presynaptic terminal molecule that accumulates in the plaques of Alzheimer's disease. Recent studies have shown that a mutation in NACP is associated with familial Parkinson's disease, and that Lewy bodies are immunoreactive with antibodies against this molecule. To clarify the patterns of accumulation and differences in abnormal compartmentalization, we studied NACP immunoreactivity using double immunolabeling and laser scanning confocal microscopy in the cortex of patients with various neurodegenerative disorders. In Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease, NACP was found to immunolabel cortical Lewy bodies, abnormal neurites, and dystrophic neurites in the plaques. Double-labeling studies showed that all three of these neuropathological structures also contained ubiquitin, synaptophysin, and neurofilament (but not tau) immunoreactivity. In contrast, neurofibrillary tangles, neuropil threads, Pick bodies, ballooned neurons, and glial tangles (most of which were tau positive) were NACP negative. These results support the view that NACP specifically accumulates in diseases related to Lewy bodies such as Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease and suggests a role for this synaptic protein in the pathogenesis of neurodegeneration.

Spillantini, M. G., R. A. Crowther, et al. (1998). "Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies." Neurosci Lett 251(3): 205-8.
Alpha-synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that alpha-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that alpha-synucleinopathies constitute a major class of human neurodegenerative disorder.

Spillantini, M. G., R. A. Crowther, et al. (1998). "alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies." Proc Natl Acad Sci U S A 95(11): 6469-73.
Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

Shibayama-Imazu, T., K. Ogane, et al. (1998). "Distribution of PNP 14 (beta-synuclein) in neuroendocrine tissues: localization in Sertoli cells." Mol Reprod Dev 50(2): 163-9.
Phosphoneuroprotein (PNP 14) is abundant in the central nervous system and is localized at nerve endings but not in synaptic vesicles. In this study, we examined the presence of PNP 14 in various endocrine tissues of the rat. PNP 14 was not detected in the endocrine cells of the intestine, testes, or adrenal gland, but it was present in axon terminals in both the medulla of the adrenal gland and the anterior pituitary gland. When testes were stained with PNP 14-specific antibodies by an indirect immunofluorescence method, PNP 14 was found in Sertoli cells of the testes, associated with fibrillar structures. PNP 14 was also detected in cultured Sertoli cells with a fibrillar pattern in the cytoplasm and around the nuclei. The fibrillar structure did not resemble actin stress fibers, microtubules, or intermediate filaments. The amount of PNP 14 in the testis changed with development. It increased markedly during the first 4 weeks after birth and then decreased. During the first 4 weeks after birth, spermatogonia undergo two rounds of meiosis. It is possible, therefore, that PNP 14 might be a factor related to meiosis.

Riess, O., R. Jakes, et al. (1998). "Genetic dissection of familial Parkinson's disease." Mol Med Today 4(10): 438-44.
In the past few years, the genetic contribution to Parkinson's disease (PD) has gained major attention and has resulted in the identification of the first mutant gene, called alpha-synuclein, involved in the pathogenesis of autosomal-dominant PD. alpha-Synuclein is a major component of Lewy bodies, which are a neuropathological feature of PD. Furthermore, deletions in the parkin gene have been identified as the primary cause in rare forms of autosomal-recessive juvenile PD. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and metabolism of xenobiotics is now technically possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of PD at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.

Polymeropoulos, M. H. (1998). "Autosomal dominant Parkinson's disease." J Neurol 245(11 Suppl 3): P1-3.
Multiple factors have been hypothesized over the years to be contributory and or causative for Parkinson's disease (PD). Hereditary factors, although originally discounted, have recently emerged in the focus of PD research. The study of a large Italian family with PD using a genome scan approach led to the mapping of a PD susceptibility gene to the 4q21-q23 genomic region, where the gene for alpha-synuclein was previously mapped. Mutation analysis of the alpha-synuclein in four unrelated families with PD revealed a missense mutation segregating with the illness. Alpha-synuclein is an abundant presynaptic protein of the human brain of unknown function. It is conceivable that the mutation identified in the PD families may result in self-aggregation and or decreased degradation of the protein, leading to the development of intracytoplasmic inclusion bodies and eventually to neuronal cell death. Moreover, the discovery of a mutation in the synuclein gene may offer us new insights into the understanding of the pathways that lead to neuronal degeneration.

Polymeropoulos, M. H. (1998). "Autosomal dominant Parkinson's disease and alpha-synuclein." Ann Neurol 44(3 Suppl 1): S63-4.
Multiple factors have been hypothesized over the years to be contributory and/or causative for Parkinson's disease (PD). Hereditary factors, although originally discounted, have recently emerged in the focus of PD research. The study of a large Italian family with PD using a genome scan approach led to the mapping of a PD susceptibility gene to the 4q21-q23 genomic region, where the gene for alpha-synuclein was previously mapped. Mutation analysis of the alpha-synuclein in four unrelated families with PD revealed a missense mutation segregating with the illness. Alpha-synuclein is an abundant presynaptic protein in the human brain with unknown function. It is conceivable that the mutation identified in the PD families may result in self-aggregation and/or decreased degradation of the protein, leading to the development of intracytoplasmic inclusion bodies and eventually to neuronal cell death. Moreover, the discovery of a mutation in the synuclein gene may offer us new insights in the understanding of the pathways that lead to neuronal degeneration.

Parsian, A., B. Racette, et al. (1998). "Mutation, sequence analysis, and association studies of alpha-synuclein in Parkinson's disease." Neurology 51(6): 1757-9.
A mutation within the alpha-synuclein gene on human chromosome 4 has been reported to segregate with PD in an Italian family. We screened a sample of familial cases of PD for mutation in the alpha-synuclein gene. None of the familial cases of PD carried a mutation within the alpha-synuclein gene, and no association was detected between PD and alleles of a dinucleotide repeat marker within the alpha-synuclein gene. We conclude that variation within the alpha-synuclein gene does not play a significant role in the risk for PD in our sample.

Paik, S. R., J. H. Lee, et al. (1998). "Self-oligomerization of NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer's disease amyloid, observed in the presence of a C-terminal A beta fragment (residues 25-35)." FEBS Lett 421(1): 73-6.
NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer's disease (AD) amyloid, also known as alpha-synuclein, was suggested to seed amyloid plaque formation in AD by stimulating A beta aggregation. We have demonstrated that NACP experienced self-oligomerization only in the presence of a modified A beta fragment (A beta25-35) by using dicyclohexylcarbodiimide. This NACP oligomerization, appearing as a discrete ladder on a Tricine SDS-PAGE, was not observed with other A beta peptides such as the reverse peptide A beta35-25 and A beta1-40, indicating this process was specific not only for the C-terminal peptide sequence of the A beta but also for its orientation. It might be, therefore, suggested that the NACP self-oligomers formed only in the presence of a N-terminally truncated A beta peptide could act as a nucleation center for plaque formation during AD development.

Ninkina, N. N., M. V. Alimova-Kost, et al. (1998). "Organization, expression and polymorphism of the human persyn gene." Hum Mol Genet 7(9): 1417-24.
Persyn is a recently identified member of the synuclein family with a distinct pattern of expression during pre- and postnatal development of the mouse peripheral and central nervous systems. As with other synucleins, persyn is believed to be involved in the pathogenesis of human neurodegenerative diseases. However, in contrast to other synucleins, high levels of persyn mRNA expression were also found in advanced breast carcinomas, suggesting an involvement of the encoded protein in breast tumour progression. Here we have used an antibody specific to human persyn to demonstrate that the level of this protein is increased in ageing cerebral cortex and in breast tumours. We cloned, characterized and sequenced the human persyn genomic locus and localized it to the long arm of chromosome 10 in the q23.2-q23.3 region. Sequence information was used to search for specific mutations in the protein coding regions of persyn mRNA and the persyn gene in breast tumours and tumour cell lines. No tumour-specific mutations were found, but two linked polymorphisms in the coding region were detected, both in mRNA and exons III and IV of the gene. These results suggest that development of breast tumours correlates with overexpression of the wild-type persyn protein. Detailed characterization of the human persyn locus is important for further studies of the involvement of persyn in neurodegeneration and malignancy.

Nakajo, S. and K. Nakaya (1998). "[New aspect of neuron-specific proteins, synucleins and PNP 14, in neurodenerative diseases]." Seikagaku 70(5): 370-5.

Mizuno, Y., H. Yoshino, et al. (1998). "Mitochondrial dysfunction in Parkinson's disease." Ann Neurol 44(3 Suppl 1): S99-109.
This review discusses the etiology and pathogenesis of Parkinson's disease (PD). Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to nigral neuronal death in PD. Complex I deficiency has been reported by several groups and appears to be one of the basic abnormalities responsible for mitochondrial failure. The principal question is whether or not complex I deficiency is primary or secondary. The second question is whether or not complex I deficiency is localized in the nigrostriatal system or is systemically present. It is our impression that complex I deficiency is not the primary cause but that its deficiency appears to be systemic. The primary cause may be the combination of genetic background and potential nigral neurotoxins. Exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared to systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. To explore the genetic risk factors of sporadic PD, studies on familial PD and parkinsonism are important. Recently, an autosomal dominant form of familial PD was found to be caused by point mutations of the alpha-synuclein gene, and an autosomal recessive familial parkinsonism was mapped to the long arm of chromosome 6 near the Mn-SOD gene locus. Information obtained in these familial cases will contribute to the research on sporadic PD.

Mezey, E., A. M. Dehejia, et al. (1998). "Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease." Mol Psychiatry 3(6): 493-9.
A missense mutation in the human alpha synuclein gene was recently identified in some cases of familial Parkinson's disease (FPD). We have developed an antibody that recognizes the C-terminal 12 amino acids of the human alpha synuclein protein and have demonstrated that alpha synuclein is an abundant component of the Lewy bodies found within the degenerating neurons of patients with Parkinson's disease (PD). The presence of alpha synuclein in Lewy bodies of sporadic PD patients suggests a central role for alpha synuclein in the pathogenesis of PD.

Mezey, E., A. Dehejia, et al. (1998). "Alpha synuclein in neurodegenerative disorders: murderer or accomplice?" Nat Med 4(7): 755-7.

Lucotte, G., G. Mercier, et al. (1998). "Lack of mutation G209A in the alpha-synuclein gene in French patients with familial and sporadic Parkinson's disease." J Neurol Neurosurg Psychiatry 65(6): 948-9.

Lozano, A. M., A. E. Lang, et al. (1998). "New developments in understanding the etiology of Parkinson's disease and in its treatment." Curr Opin Neurobiol 8(6): 783-90.
Important recent advances have been made in understanding the etiology and pathogenesis of Parkinson's disease, as well as in developing novel treatments. Two newly identified genes, alpha-synuclein and parkin, have been linked to parkinsonism. In addition, disturbances to the normal basal ganglia circuits in Parkinson's patients are being described at both anatomical and physiological levels. These developments provide a strong scientific basis for novel medical and surgical strategies to treat the profound motor disturbances in patients with Parkinson's disease.

Liu, Y. and D. Schubert (1998). "Steroid hormones block amyloid fibril-induced 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan exocytosis: relationship to neurotoxicity." J Neurochem 71(6): 2322-9.
Perhaps the most reproducible early event induced by the interaction of amyloid beta peptide (A beta) with the cell is the inhibition of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. We recently demonstrated that cytotoxic amyloid peptides such as A beta and human amylin inhibit cellular MTT reduction by dramatically enhancing MTT formazan exocytosis. We now show the following: (a) Insulin and glucagon, when converted to fibrils with beta-pleated sheet structure, induce MTT formazan exocytosis that is indistinguishable from that induced by A beta. NAC35, an amyloidogenic fragment of alpha-synuclein (or NACP), also induces MTT formazan exocytosis. (b) All protein fibrils with the beta-pleated sheet structure examined are toxic to rat hippocampal neurons. (c) Many sterol sex hormones (e.g., estradiol and progesterone) block amyloid fibril-enhanced MTT formazan exocytosis as well as MTT formazan exocytosis in control cells by acting at a common late step in the exocytic pathway. Steroids fail, however, to protect hippocampal neurons from acute amyloid fibril toxicity. These findings suggest that the ability to enhance MTT formazan exocytosis and to induce neurotoxicity are common biological activities of protein fibrils with beta-pleated sheet structure but that enhanced MTT formazan exocytosis is not sufficient for acute A beta neurotoxicity.

Lippa, C. F., H. Fujiwara, et al. (1998). "Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes." Am J Pathol 153(5): 1365-70.
Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.

Lee, J. H., H. J. Shin, et al. (1998). "Comparisons of the NACP self-oligomerizations induced by Abeta25-35 in the presence of dicyclohexylcarbodiimide and N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline." Neurochem Res 23(11): 1427-34.
NACP, the precursor protein of the non-amyloid beta/A4 protein (Abeta) component of Alzheimer's disease (AD) amyloid, also known as alpha-synuclein was shown to undergo self-oligomerization only in the presence of a modified Abeta fragment (residues 25 35) by using a relatively hydrophobic coupling reagent, dicyclohexylcarbodiimide (DCCD). Since the oligomerization not only required a relatively high concentration of DCCD but also its efficiency was suppressed even at a slightly basic pH of 7.5, another coupling reagent called N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline (EEDQ) was examined in order to make use of this technique to access the functional aspects of NACP in vitro by exploring more accurate and reproducible reaction conditions. The EEDQ also gave rise to the NACP oligomerization only in the presence of Abeta25-35 among the variously modified Abeta peptides. The reagent was about three times more effective than DCCD in terms of its optimal concentration to visualize the oligomers. In addition, its oligomerizing potency was not affected by the basic condition. Although physiological and pathological significance of the NACP self-oligomerization are currently unknown, this dramatic phenomenon and its visualization technique could shed light on the determination of molecular relationships of NACP with various intracellular or extracellular biomolecules related to the pathological conditions of Alzheimer's and Parkinson's diseases.

Lavedan, C., S. Buchholtz, et al. (1998). "Absence of mutation in the beta- and gamma-synuclein genes in familial autosomal dominant Parkinson's disease." DNA Res 5(6): 401-2.

Lavedan, C., E. Leroy, et al. (1998). "Genomic organization and expression of the human beta-synuclein gene (SNCB)." Genomics 54(1): 173-5.
The beta-synuclein protein is highly homologous to the alpha-synuclein protein for which two mutations were reported in some familial cases of Parkinson disease. It has been shown that both alpha- and beta-synucleins may be able to inhibit phospholipase D2 selectively. We have observed that the beta-synuclein gene (HGMW-approved symbol, SNCB) is highly expressed in brain including the substantia nigra, the main region of neuronal degeneration in patients with Parkinson disease. We have determined the intron-exon structure of the beta-synuclein gene and established sequencing assays that will facilitate the search for mutations in the beta-synuclein gene in patients with Parkinson disease or other neurodegenerative disorders.

Lavedan, C. (1998). "The synuclein family." Genome Res 8(9): 871-80.
The synuclein gene family recently came into the spotlight, when one of its members, alpha-synuclein, was found to be mutated in several families with autosomal dominant Parkinson's disease (PD). A peptide of the alpha-synuclein protein had been characterized previously as a major component of amyloid plaques in brains of patients with Alzheimer's disease (AD). The mechanism by which this presynaptic protein is involved in the two most common neurodegenerative disorders, AD and PD, remains unclear. Remarkably, another member of this gene family, gamma-synuclein, has been shown to be overexpressed in breast carcinomas and may also be overexpressed in ovarian cancer. The possible involvement of the synuclein proteins in the etiology of common human diseases has raised exciting questions and is the subject of intense investigation. Details of the properties of any member of the synuclein family may provide useful information for understanding the characteristics and function of other family members. The present review offers a synopsis of the current state of knowledge of all synuclein family members in different species.

Lavedan, C., E. Leroy, et al. (1998). "Identification, localization and characterization of the human gamma-synuclein gene." Hum Genet 103(1): 106-12.
We have identified and characterized a new member of the human synuclein gene family, gamma-synuclein (SNCG). This gene is composed of five exons, which encode a 127 amino acid protein that is highly homologous to alpha-synuclein, which is mutated in some Parkinson's disease families, and to beta-synuclein. The gamma-synuclein gene is localized to chromosome 10q23 and is principally expressed in the brain, particularly in the substantia nigra. We have determined its genomic sequence, and established conditions for sequence analysis of each of the exons. The gamma-synuclein gene, also known as BCSG1, was recently found to be overexpressed in advanced infiltrating carcinoma of the breast. Our survey of the EST database indicated that it might also be overexpressed in an ovarian tumor.

Lavedan, C., A. Dehejia, et al. (1998). "Contig map of the Parkinson's disease region on 4q21-q23." DNA Res 5(1): 19-23.
We have constructed a yeast artificial chromosome contig (YAC) map of human chromosome 4q21-q23 across the Parkinson's disease region by combining molecular and fluorescence in situ hybridization techniques. This map contains 55 YACs and 51 molecular markers, including 23 polymorphic markers. We have also isolated one P1 and 33 bacterial artificial chromosomes located within this contig. Plasmid libraries were generated from 11 of these BAC and P1 clones, and 614 random plasmid clones were sequenced for a total of about 200 kb. This contig allowed us to precisely determine the location of 18 transcripts within the D4S2460-D4S2986 interval, including the alpha-synuclein gene found to be mutated in some families with Parkinson's disease.

Langston, J. W., S. Sastry, et al. (1998). "Novel alpha-synuclein-immunoreactive proteins in brain samples from the Contursi kindred, Parkinson's, and Alzheimer's disease." Exp Neurol 154(2): 684-90.
A specific mutation (A53T) in the encoding region for alpha-synuclein has been identified in a large multigenerational family with an autosomal dominant parkinsonism known as the Contursi kindred. In this study, we used a monoclonal antibody directed against alpha-synuclein in order to identify novel proteins in the brain of an affected member of this kindred who had come to autopsy. Homogenates from the frontal cortex and caudate nucleus were examined using Western blot techniques and compared to matched autopsy specimens from control subjects and patients with various forms of parkinsonism. Western blots, using a 15-min exposure time, revealed the expected 19-kDa band representing alpha-synuclein in all brain samples examined. However, a novel band in the 36-kDa range was also present in the Contursi brain which was not seen in cortex or caudate from control brains or in frontal cortex from 14 cases of typical Parkinson's disease. With a 24-h exposure time, this band was faintly seen in the caudate nucleus of three of the Parkinson's disease cases. Surprisingly, the 36-kDa band (as well as other high-molecular-weight bands) was also present in frontal cortex and caudate nucleus in 3 additional cases that met diagnostic criteria for both Parkinson's disease and Alzheimer's disease. A preliminary analysis of samples from the frontal cortex of 10 Alzheimer's disease cases revealed a 36-kDa band in only one instance. The identification of novel alpha-synuclein-immunoreactive bands in these various forms of parkinsonism may open new research avenues for exploring the relationship between abnormal protein deposition in the brain and one or more neurodegenerative disorders, including the Contursi form of familial parkinsonism.

Kruger, R., W. Kuhn, et al. (1998). "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease." Nat Genet 18(2): 106-8.

Jones, A. C., Y. Yamamura, et al. (1998). "Autosomal recessive juvenile parkinsonism maps to 6q25.2-q27 in four ethnic groups: detailed genetic mapping of the linked region." Am J Hum Genet 63(1): 80-7.
Parkinson disease (PD) is a common neurodegenerative condition associated with degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. There is increasing evidence that genetic factors play a role in the etiology of PD, although genetic heterogeneity is likely. An autosomal dominant syndrome with many similarities to sporadic PD has been mapped to 4q21-22 in a large Italian pedigree and has been found to be due to mutation of the alpha-synuclein gene. However, this gene appears to account for only a minority of PD, and a susceptibility locus for autosomal dominant parkinsonism has recently been mapped, on 2p13. Autosomal recessive juvenile parkinsonism (JP), which shows marked clinical similarity to PD, maps to 6q25.2-q27. We found linkage to this region in a group of 15 families from four distinct ethnic backgrounds. A full genomic screen excluded other candidate regions. We have constructed a detailed genetic map of the linked region and have mapped the position of the manganese superoxide dismutase gene (SOD2). Recombination events restricted the JP locus to a 6.9-cM region and excluded SOD2. The apparent homozygosity for null alleles at D6S955 in one family suggested a deletion and finer localization of the JP locus.

Jensen, P. H., M. S. Nielsen, et al. (1998). "Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation." J Biol Chem 273(41): 26292-4.
The presynaptic protein alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease. First, two missense mutations A30P and A53T cause inheritable early onset Parkinson's disease in some families. Secondly, alpha-synuclein is present in Lewy bodies of affected nerve cells in the predominant sporadic type of Parkinson's disease as well as in dementia with Lewy bodies. We demonstrate in the rat optic system that a portion of alpha-synuclein is carried by the vesicle-moving fast component of axonal transport and that it binds to rat brain vesicles through its amino-terminal repeat region. We find alpha-synuclein with the A30P mutation of familial Parkinson's disease devoid of vesicle-binding activity and propose that mutant alpha-synuclein may accumulate, leading to assembly into Lewy body filaments.

Jensen, P. H. and J. Gliemann (1998). "[Parkinson disease. Alpha-synuclein is the first molecular help]." Ugeskr Laeger 160(35): 5054-5.

Jenner, P. and C. W. Olanow (1998). "Understanding cell death in Parkinson's disease." Ann Neurol 44(3 Suppl 1): S72-84.
Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, alpha-synuclein) proteins may lead to their aggregation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both alpha-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.

Jenco, J. M., A. Rawlingson, et al. (1998). "Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins." Biochemistry 37(14): 4901-9.
Two widely expressed mammalian phosphatidylcholine (PC)-specific phospholipases D (PLD), PLD1 and PLD2, have been identified. Recombinantly expressed PLD2 has high basal activity and is insensitive to GTP-binding protein activators of PLD1 [Colley, W. C., et al. (1997) Curr. Biol. 7, 191-201]. To investigate the regulation of PLD2 we isolated PLD2, from mouse brain by immunoaffinity chromatography. The native and recombinant proteins have indistinguishable properties: PLD2 is potently activated by phosphoinositides with a vicinal 4,5-phosphate pair but is not stimulated by guanosine 5'-O-(3-thio triphosphate)-activated ADP-ribosylation factor-1, Rho family GTP-binding proteins, or protein kinases C-alpha, or -beta1. We used recombinant PLD2 in a reconstitution assay to search for regulators in cell and tissue extracts. Bovine brain contains a heat-stable protein factor that inhibits PLD2 activity in vitro. This factor was purified to homogeneity and identified as a mixture of alpha- and beta-synucleins by microsequencing and Western blotting. Recombinantly expressed alpha- and beta-synucleins inhibit PLD2 activity in vitro (K0.5 10 nM). Inhibition is not overcome by the protein or lipid activators of PLD1. Synucleins have been implicated in Parkinson's and Alzheimer's diseases. Our findings suggest that inhibition of PLD2 may be a function of synucleins. Modulation of PLD2 activity by synucleins may play a role in some aspects of the pathophysiologies that characterize these neurodegenerative diseases.

Jakowec, M. W., G. M. Petzinger, et al. (1998). "The native form of alpha-synuclein is not found in the cerebrospinal fluid of patients with Parkinson's disease or normal controls." Neurosci Lett 253(1): 13-6.
Alpha-synuclein has recently been shown to be a major constituent of Lewy bodies in Parkinson's disease (PD). This observation led us to investigate the possibility that its detection in the cerebrospinal fluid (CSF) could be used as a marker for Lewy bodies in the central nervous system. In this study we determined the pattern of expression of alpha-synuclein in patients with sporadic Parkinson's disease (PD) and normal controls, using western immunoblotting in conjunction with an antibody that recognizes the carboxyl terminal of alpha-synuclein protein. The native 19 kDa band normally seen in brain homogenates was not found in the CSF of either parkinsonian patients or control subjects. However, a novel band was observed, which migrated at a position in the range of 42 kDa in CSF from both patients and controls. We conclude that alpha-synuclein cannot be used as a biomarker for Lewy bodies during life. However, further characterization of the 42 kDa protein may be of interest.

Ishimaru, H., K. Ueda, et al. (1998). "Changes in presynaptic protein NACP/alpha-synuclein in an ischemic gerbil hippocampus." Brain Res 788(1-2): 311-4.
We observed temporal changes in NACP (precursor protein of non-Abeta component of Alzheimer's disease amyloid), a presynaptic protein a.k. a. alpha-synuclein, in the hippocampus after 5 min ischemia. Intense NACP immunoreactivity was seen transiently around cerebral blood vessels in the CA1 subfield on day 4, and NACP-positive unusual tubal and chain-like structures developed on month 6. We suggest that the changes in NACP may play an important role in the ischemic pathogenesis.

Iseki, E., W. Marui, et al. (1998). "Degenerative terminals of the perforant pathway are human alpha-synuclein-immunoreactive in the hippocampus of patients with diffuse Lewy body disease." Neurosci Lett 258(2): 81-4.
We investigated the hippocampal pathology in diffuse Lewy body disease (DLBD) using alpha-synuclein immunohistochemistry. Ubiquitin-positive intrahippocampal structures caused by the degeneration of terminal axons of the perforant pathway were observed to be alpha-synuclein immunoreactive. These alpha-synuclein-positive degenerative terminals contained granulo-filamentous or vesiculo-tubular components similar to those of Lewy bodies (LB) immunoelectron microscopically, suggesting that alpha-synuclein may abnormally aggregate into filamentous or membranous cytoskeletal components including neurofilaments and synaptic vesicles in DLBD. A 'dying back' degenerating process due to a blockage of axonal transport may explain why the degenerative terminals and LB share similar alpha-synuclein-positive components, but the origin cells of the perforant pathway contain only a few LB.

Irizarry, M. C., W. Growdon, et al. (1998). "Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity." J Neuropathol Exp Neurol 57(4): 334-7.
A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.

Hsu, L. J., M. Mallory, et al. (1998). "Expression pattern of synucleins (non-Abeta component of Alzheimer's disease amyloid precursor protein/alpha-synuclein) during murine brain development." J Neurochem 71(1): 338-44.
The non-Abeta component of Alzheimer's disease amyloid precursor protein (NACP) is predominantly a neuron-specific presynaptic protein that may play a central role in neurodegeneration because NACP fragments are found in Alzheimer's disease amyloid and a mutation in the NACP gene is associated with familial Parkinson's disease. In addition, NACP may play an important role during synaptogenesis and CNS development. To understand better the patterns of NACP expression during development, we analyzed the levels of this protein as well as the levels of another synaptic protein (synaptophysin) by ribonuclease protection assay, western blotting, and immunocytochemistry in fetal, juvenile, and adult mouse brain. From embryonic day 12 to 15, there was a slight increase, which was then followed by a more dramatic increase at later time points. Immunocytochemical staining for NACP increases throughout these stages as well. Although NACP appeared early in CNS development, synaptophysin levels started to rise at a later stage. These findings support the contention that NACP might be important for CNS development. Furthermore, the cytosolic component of NACP precedes the particulate component in development, indicating that a redistribution of the protein to the membrane fraction may be important for events later in neuronal development and in synaptogenesis.

Hong, L., H. W. Ko, et al. (1998). "The cDNA cloning and ontogeny of mouse alpha-synuclein." Neuroreport 9(6): 1239-43.
Alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease. To investigate the role of alpha-synuclein in the brain, the cDNA clone encoding the mouse cognate of the human alpha-synuclein was isolated from a mouse brain cDNA library. The open reading frame coded for 140 amino acids that share 95% identity with human alpha-synuclein. Northern blot analysis showed that alpha-synuclein mRNA was primarily expressed in brain and spleen of adult mouse. In situ hybridization histochemistry revealed the highest expression of alpha-synuclein mRNA in the hippocampal formation and neocortex of the adult mouse. alpha-Synuclein mRNA expression in the brain was first observed in the hippocampus and neocortex on postnatal day 1. Levels of alpha-synuclein mRNA in these forebrain areas were nearly maximal at postnatal day 7 and remained relatively high until the adult stage. alpha-Synuclein mRNA was expressed in the liver transiently during embryogenesis.

Ho, S. L. and M. H. Kung (1998). "G209A mutation in the alpha-synuclein gene is rare and not associated with sporadic Parkinson's disease." Mov Disord 13(6): 970-1.

Higuchi, S., H. Arai, et al. (1998). "Mutation in the alpha-synuclein gene and sporadic Parkinson's disease, Alzheimer's disease, and dementia with lewy bodies." Exp Neurol 153(1): 164-6.
Recently, alpha-synuclein attracted attention when Polymeropoulos and colleagues identified a missense mutation of this gene (Science 276:2045-2047, 1997), which is responsible for a form of early-onset familial Parkinson's disease (PD). Immunohistochemically, alpha-synuclein is localized in Lewy bodies, characteristic brain pathology of PD, dementia with Lewy bodies (DLB), and Alzheimer's disease (AD), suggesting that this protein may link these common neurological diseases. Exploration of the possibility that the same mutation of the alpha-synuclein gene as that in familial PD (Ala53Thr) may also confer susceptibility to sporadic PD, DLB, and AD revealed the mutation in none of the samples of 329 cases and 230 controls examined, suggesting that this mutation is not involved in these neurological diseases.

Higgins, J. J., I. Litvan, et al. (1998). "Progressive supranuclear gaze palsy is in linkage disequilibrium with the tau and not the alpha-synuclein gene." Neurology 50(1): 270-3.
We studied two candidate genes, tau (tau) and alpha-synuclein (SNCA), for evidence of linkage disequilibrium on a group of unrelated individuals with progressive supranuclear palsy (PSP) and a group of age-matched control subjects. The tau alpha1 allele and the tau alpha1alpha1 genotype were overrepresented in individuals with PSP and the tau polymorphism was in linkage disequilibrium with the PSP disease locus when a recessive inheritance model was employed. We also report a lack of evidence to support linkage disequilibrium between PSP and the SNCA candidate Parkinson's disease gene on chromosome 4q21-q23.

Hellman, N. E., E. A. Grant, et al. (1998). "Failure to replicate a protective effect of allele 2 of NACP/alpha-synuclein polymorphism in Alzheimer's disease: an association study." Ann Neurol 44(2): 278-81.
Recently, a dinucleotide repeat polymorphism was identified in the promoter of the nonamyloid component of plaques (NACP) gene, and it was shown that the NACP allele 2 was significantly associated with healthy elderly control individuals with at least one apolipoprotein E epsilon4 allele, suggesting a protective role for this allele in Alzheimer's disease. We genotyped the same NACP polymorphism in a comparable number of individuals diagnosed with dementia of the Alzheimer's type and in healthy, elderly controls. In our analysis, however, no protective effect for NACP allele 2, or any of the other NACP alleles, was observed.

Hashimoto, M., L. J. Hsu, et al. (1998). "Human recombinant NACP/alpha-synuclein is aggregated and fibrillated in vitro: relevance for Lewy body disease." Brain Res 799(2): 301-6.
The precursor of non-amyloid beta protein component of Alzheimer's disease amyloid (NACP/alpha-synuclein) is aggregated and fibrillated under certain conditions, i.e., increasing time lag, high temperature and low pH. These in vitro aggregates form Thioflavine-S-positive filamentous structures, reminiscent of amyloid-like fibrils. Since some Lewy bodies in Parkinson's disease display Thioflavine-S reactivity, our results may suggest that amyloidogenic properties of NACP/alpha-synuclein may play a crucial role in pathogenesis of disorders with Lewy bodies such as Parkinson's disease.

Hardy, J. and K. Gwinn-Hardy (1998). "Genetic classification of primary neurodegenerative disease." Science 282(5391): 1075-9.
Review During the past 10 years (the "decade of the brain"), some of the genetic causes of many of the primary neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion disease, and many ataxic syndromes, have been found. These breakthroughs mean that for many of these diseases we now know the initiating trigger as well as the final outcome. These diseases have many pathological mechanisms in common, and there may be relatively few pathways to neuronal death seen in these disorders. Thus, treatment strategies developed for a particular disease may be found to have efficacy in more than one disorder.

Gomez-Tortosa, E., A. O. Ingraham, et al. (1998). "Dementia with Lewy bodies." J Am Geriatr Soc 46(11): 1449-58.
In the last decade, a new degenerative dementia, probably the second most common after Alzheimer's disease (AD), has been increasingly recognized under the consensus name of dementia with Lewy bodies (DLB). This article reviews current clinical, genetic, and pathological DLB data and indicates directions for future research. DLB overlaps in clinical, pathological, and genetic features with AD and Parkinson's disease (PD). Clinically, it is characterized by progressive cognitive impairment with significant fluctuations in alertness, parkinsonism, and psychosis with recurrent hallucinations. The neuropathological hallmarks are the intracytoplasmic inclusions in substantia nigra typical of PD, known as Lewy bodies (LB) but distributed widely throughout paralimbic and neocortical regions. Most of the cases also coexist with a plaque predominant AD. It is probably the unique and differential distribution of the lesions throughout cortical and subcortical structures in each of these disorders that supports a specific clinical syndrome and may ultimately prove most useful in understanding their different etiologies. Several genes have recently been implicated in LB formation. Special interest arises from mutations in the alpha-synuclein gene, which appears to be responsible for autosomal dominant PD in several kindreds. This gene encodes a presynaptic protein, a fragment of which is present in AD plaques. Recent studies show intense and quite specific alpha-synuclein immunoreactivity in LB and related neurites, suggesting a potential role of this protein in the aggregation or precipitation of LB inclusions.

Goedert, M. and M. G. Spillantini (1998). "Lewy body diseases and multiple system atrophy as alpha-synucleinopathies." Mol Psychiatry 3(6): 462-5.

Goedert, M., M. G. Spillantini, et al. (1998). "Filamentous nerve cell inclusions in neurodegenerative diseases." Curr Opin Neurobiol 8(5): 619-32.
Recent work has shown that abnormal filamentous inclusions within some nerve cells is a characteristic shared by Alzheimer's disease, some frontotemporal dementias, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, as well as Huntington's disease and other trinucleotide repeat disorders. This suggests that in each of these disorders, the affected nerve cells degenerate as a result of these abnormal inclusions. Except for trinucleotide repeat disorders, the filaments involved have been shown to consist of either the microtubule-associated protein tau or alpha-synuclein. Over the past year, mutations in the genes for tau and alpha-synuclein have been identified as the genetic causes of some familial forms of frontotemporal dementia and Parkinson's disease, respectively. The discovery last year of neuronal intranuclear inclusions in Huntington's disease and other disorders with expanded glutamine repeats has suggested a unifying mechanism underlying the pathogenesis of this class of neurodegenerative diseases.

Goedert, M., R. Jakes, et al. (1998). "Intraneuronal filamentous tau protein and alpha-synuclein deposits in neurodegenerative diseases." Biochem Soc Trans 26(3): 463-71.

Gasser, T. (1998). "Genetics of Parkinson's disease." Clin Genet 54(4): 259-65.
A genetic contribution to the etiology of Parkinson's disease (PD) is now well established, based on the demonstration of a familial aggregation of the disease as demonstrated by several case control and twin studies, and on the description of large multigenerational families, in whom PD is inherited in a Mendelian fashion. In a few families with autosomal dominant inheritance and typical Lewy-body pathology, a gene locus has been mapped to the long arm of chromosome 4, and mutations have been identified in the gene for alpha-synuclein. A gene causing autosomal recessive parkinsonism of juvenile onset has been mapped to chromosome 6, and the causative gene has been identified and named Parkin. This form of parkinsonism differs pathologically from the sporadic disease, as no Lewy bodies are found in the substantia nigra. A third locus, again in families with dominant inheritance, typical Lewy-body pathology and late onset, has been mapped to chromosome 2pl3. At present, there is no evidence that any of these genes for familial Parkinsonian syndromes have a direct role in the etiology of the common sporadic form of PD. However, the elucidation of the molecular sequence of events leading to nigral degeneration in these inherited cases is likely to shed light on the molecular pathogenesis of this common neurodegenerative disorder.

Gasser, T. (1998). "Genetics of Parkinson's disease." Ann Neurol 44(3 Suppl 1): S53-7.
A genetic contribution to the etiology of Lewy body Parkinson's disease (PD) is now well established, based on the demonstration of a familial aggregation of the disease by case-control and twin studies and on the description of large multigenerational families in whom clinically and pathologically typical PD is inherited in an autosomal dominant fashion. In the largest of these families, a gene locus has been mapped to the long arm of chromosome 4 and a putative disease-causing mutation has been identified in the gene for alpha-synuclein. However, analysis of a large number of individuals with sporadic and familial PD suggests that a mutation in this gene is a very rare cause of the disorder, either familial or sporadic. Another locus for autosomal dominantly inherited Lewy body PD has recently been mapped to chromosome 2p13. Possible strategies for the identification of further PD genes are discussed.

Gasser, T., B. Muller-Myhsok, et al. (1998). "A susceptibility locus for Parkinson's disease maps to chromosome 2p13." Nat Genet 18(3): 262-5.
Parkinson's disease (PD) is a common degenerative neurologic disorder, which is pathologically characterized by a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta, and the presence of characteristic eosinophilic inclusions, known as Lewy-bodies in affected brain areas. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease. Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects and questioned earlier studies which had denied such influences. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically and in some cases also neuropathologically. Recently, a disease locus has been mapped to chromosome 4q21-22 in a large Mediterranean pedigree, in which disease expression is clinically and pathologically within the spectrum of sporadic PD; being atypical only for a relatively young mean age at onset of 46 years and rapid course of 10 years from onset to death. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding alpha-synuclein. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkinsonism was not linked to the 4q-locus and was not associated with the alpha-synuclein mutation (unpublished data). We describe a different genetic locus that appears to be involved in the development of parkinsonism closely resembling sporadic PD including a similar mean age of onset (59 years in the families, 59.7 years in sporadic PD; ref. 12). This locus was detected in a group of families of European origin. In two of these families, there is genetic evidence for a common founder. The penetrance of the mutation appears to be low, most likely below 40%. This is compatible with a possible role of this locus not only in familial, but also in typical (sporadic) PD.

Gai, W. P., J. H. Power, et al. (1998). "Multiple-system atrophy: a new alpha-synuclein disease?" Lancet 352(9127): 547-8.

Farrer, M., F. Wavrant-De Vrieze, et al. (1998). "Low frequency of alpha-synuclein mutations in familial Parkinson's disease." Ann Neurol 43(3): 394-7.
A mutation in exon 4 of the alpha-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.

El-Agnaf, O. M., M. D. Curran, et al. (1998). "Mutation screening in exons 3 and 4 of alpha-synuclein in sporadic Parkinson's and sporadic and familial dementia with Lewy bodies cases." Neuroreport 9(17): 3925-7.
Recently it has been reported that a missense G(88)C mutation within exon 3 and a missense G(209)A mutation within exon 4 of the alpha-synuclein gene were linked to familial Parkinson's Disease (PD). We decided to investigate if these and any other mutations in exons 3 and 4 of the alpha-synuclein gene could be detected in sixty two sporadic PD and dementia with Lewy bodies (DLB) patients. Four cases of familial DLB were also studied, two of which were from the same family. Single stranded conformational polymorphism, DNA sequencing analyses and PCR-RFLP of exons 3 and 4 failed to reveal any nucleotide changes. However, three nucleotide differences occurred in the intron 4 sequence compared to the published sequence. This study adds further support to the idea that these particular mutation in the alpha-synuclein gene are a rare case of PD and now, as we have shown here, also of DLB.

El-Agnaf, O. M., R. Jakes, et al. (1998). "Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments." FEBS Lett 440(1-2): 71-5.
Alpha-synuclein (alpha-syn) protein and a fragment of it, called NAC, have been found in association with the pathological lesions of a number of neurodegenerative diseases. Recently, mutations in the alpha-syn gene have been reported in families susceptible to an inherited form of Parkinson's disease. We have shown that human wild-type alpha-syn, mutant alpha-syn(Ala30Pro) and mutant alpha-syn(Ala53Thr) proteins can self-aggregate and form amyloid-like filaments. Here we report that aggregates of NAC and alpha-syn proteins induced apoptotic cell death in human neuroblastoma SH-SY5Y cells. These findings indicate that accumulation of alpha-syn and its degradation products may play a major role in the development of the pathogenesis of these neurodegenerative diseases.

El-Agnaf, O. M., R. Jakes, et al. (1998). "Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson's disease." FEBS Lett 440(1-2): 67-70.
Alpha-synuclein (alpha-syn) protein has been found in association with the pathological lesions of a number of neurodegenerative diseases. Recently, mutations in the alpha-syn gene have been reported in families susceptible to an inherited form of Parkinson's disease. We report here that human wild-type alpha-syn, PD-linked mutant alpha-syn(Ala30Pro) and mutant alpha-syn(Ala53Thr) proteins can self-aggregate and form amyloid-like filaments. The mutant alpha-syn forms more beta-sheet and mature filaments than the wild-type protein. These findings suggest that accumulation of alpha-syn as insoluble deposits of amyloid may play a major role in the pathogenesis of these neurodegenerative diseases.

Davidson, W. S., A. Jonas, et al. (1998). "Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes." J Biol Chem 273(16): 9443-9.
alpha-Synuclein is a highly conserved presynaptic protein of unknown function. A mutation in the protein has been causally linked to Parkinson's disease in humans, and the normal protein is an abundant component of the intraneuronal inclusions (Lewy bodies) characteristic of the disease. alpha-Synuclein is also the precursor to an intrinsic component of extracellular plaques in Alzheimer's disease. The alpha-synuclein sequence is largely composed of degenerate 11-residue repeats reminiscent of the amphipathic alpha-helical domains of the exchangeable apolipoproteins. We hypothesized that alpha-synuclein should associate with phospholipid bilayers and that this lipid association should stabilize an alpha-helical secondary structure in the protein. We report that alpha-synuclein binds to small unilamellar phospholipid vesicles containing acidic phospholipids, but not to vesicles with a net neutral charge. We further show that the protein associates preferentially with vesicles of smaller diameter (20-25 nm) as opposed to larger (approximately 125 nm) vesicles. Lipid binding is accompanied by an increase in alpha-helicity from 3% to approximately 80%. These observations are consistent with a role in vesicle function at the presynaptic terminal.

Crowther, R. A., R. Jakes, et al. (1998). "Synthetic filaments assembled from C-terminally truncated alpha-synuclein." FEBS Lett 436(3): 309-12.
Recently two point mutations in the alpha-synuclein gene have been found in familial Parkinson's disease. The characteristic fibrous neuropathological lesions of Parkinson's and other neurodegenerative diseases have been shown to stain strongly with antibodies against alpha-synuclein and extracted filaments have been labelled with anti-alpha-synuclein antibodies. In view of the close involvement of alpha-synuclein filaments with pathology, it was important to establish an in vitro assembly system. We report here that C-terminally truncated recombinant alpha-synuclein readily assembles into filaments resembling those isolated from diseased brain and suggest that truncation by proteolysis may play a role in the pathological process.

Conway, K. A., J. D. Harper, et al. (1998). "Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease." Nat Med 4(11): 1318-20.
Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.

Clayton, D. F. and J. M. George (1998). "The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease." Trends Neurosci 21(6): 249-54.
Synuclein proteins are produced, in vertebrates, by three genes.They share structural resemblance to apolipoproteins, but are abundant in the neuronal cytosol and present in enriched amounts at presynaptic terminals. Synucleins have been specifically implicated in three diseases:Alzheimer's (AD), Parkinson's (PD) and breast cancer. In AD, a peptide derived from alpha-synuclein forms an intrinsic component of plaque amyloid. In PD, an alpha-synuclein allele is genetically linked to several independent familial cases, and the protein appears to accumulate in Lewy bodies. In breast cancer, increased expression of gamma-synuclein correlates with disease progression. In songbirds, alpha-synuclein expression is correlated with plasticity in the developing song control system. Although the normal function of synucleins is unknown, a role in membrane plasticity seems likely.

Chan, P., X. Jiang, et al. (1998). "Absence of mutations in the coding region of the alpha-synuclein gene in pathologically proven Parkinson's disease." Neurology 50(4): 1136-7.
A missense mutation of the alpha-synuclein gene has been associated with parkinsonism in a large Italian kindred. Recently, alpha-synuclein was also identified in Lewy bodies. Using reverse transcribed-polymerase chain reaction (RT-PCR) technique, we sequenced the entire coding region of the alpha-synuclein gene using brain tissue from 24 pathologically proven Parkinson's disease cases. No mutations were found in any of the patients, suggesting that a mutation at the coding region of the alpha-synuclein gene is unlikely to be responsible for nigrostriatal degeneration in typical sporadic Parkinson's disease.

Chan, P., C. M. Tanner, et al. (1998). "Failure to find the alpha-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson's disease." Neurology 50(2): 513-4.
The missense G209A mutation at exon 4 of the alpha-synuclein gene was recently found to be responsible for familial Parkinson's disease (PD) in a large kindred of Italian descent. We studied 100 typical PD patients with onset before age 51, both with and without a family history of PD. We did not find this alpha-synuclein missense mutation in any patient, but it was present in a symptomatic member of the Contursi family.

Buchman, V. L., J. Adu, et al. (1998). "Persyn, a member of the synuclein family, influences neurofilament network integrity." Nat Neurosci 1(2): 101-3.

Buchman, V. L., H. J. Hunter, et al. (1998). "Persyn, a member of the synuclein family, has a distinct pattern of expression in the developing nervous system." J Neurosci 18(22): 9335-41.
The synucleins are a unique family of small intracellular proteins that have recently attracted considerable attention because of their involvement in human neurodegenerative diseases. We have cloned a new member of the synuclein family called persyn. In contrast to other synucleins, which are presynaptic proteins of CNS neurons, persyn is a cytosolic protein that is expressed predominantly in the cell bodies and axons of primary sensory neurons, sympathetic neurons, and motoneurons. Northern blotting, in situ hybridization, Western blotting, and immunohistochemistry revealed that persyn mRNA and protein are expressed in these neurons from the earliest stages of axonal outgrowth and are maintained at a high level throughout life. Persyn also becomes detectable in evolutionary recent regions of the brain by adulthood.

Buchman, V. L. (1998). "[Synucleins--the key to mechanisms of neurodegenerative diseases?]." Mol Biol (Mosk) 32(4): 592-7.

Brooks, D. J. (1998). "The early diagnosis of Parkinson's disease." Ann Neurol 44(3 Suppl 1): S10-8.
Current accepted clinical criteria for the diagnosis of Parkinson's disease (PD) provide high sensitivity for detecting parkinsonism but generally show poor specificity for identifying brainstem Lewy body disease. Biochemical markers that can be used to reliably diagnose clinical and preclinical PD have thus far been sought unsuccessfully. It is now known that some PD kindreds have a mutation of the alpha-synuclein gene, but this cannot be used as a genetic marker for most familial and sporadic cases. Functional imaging provides a means of discriminating typical from atypical PD, revealing characteristic patterns of loss of dopaminergic function. In addition, PET and SPECT show preserved levels of striatal metabolism and dopamine receptor binding in PD, whereas levels are reduced in the atypical variants. [18F]Dopa PET can also detect preclinical PD. In one series there was a reported 40% prevalence of preclinical dopaminergic dysfunction in asymptomatic adult relatives of familial PD patients. Finally, PET and SPECT can both be used to follow PD progression objectively. Such studies suggest an annual 4 to 12% loss of dopamine terminal function in early PD and a preclinical disease window of only a few years. In the future, functional imaging is likely to play an increasingly important role in assessing the efficacy of putative neuroprotective agents.

Brice, A. (1998). "[Genetics of extrapyramidal diseases]." Rev Neurol (Paris) 154(11): 739-42.

Brice, A. (1998). "[Parkinson disease: monogenic forms and genetic susceptibility factors]." Pathol Biol (Paris) 46(9): 710-2.
Parkinson's disease (PD) is one of the most frequent neurodegenerative disorders. The role of genetic factors in its pathogenesis is supported by several lines of evidence: the high concordance in twins using PET scan; the increased risk among relatives of PD patients in case control and family studies; the existence of monogenic forms of PD. the alpha-synuclein gene is involved in a rare dominant form of the disease for which a new locus has been recently mapped to chromosome 2. Early onset autosomal recessive parkinsonism, which maps to chromosome 6q, appears to be frequent in Japan and in Europe. The genes for several monogenic forms of this entity should be identified soon, providing new insight into the pathophysiology of the disease. However, it is not clear if these genes will be relevant to apparently sporadic cases. In the long term, genotyping of affected sib-pairs should permit localisation and identification of other genetic susceptibility factors. These complementary approaches will contribute to the elucidation of the mechanism of PD and should provide new targets for drug therapies.

Borden, K. L. (1998). "Structure/function in neuroprotection and apoptosis." Ann Neurol 44(3 Suppl 1): S65-71.
The three-dimensional conformation of proteins influences their potential to function correctly within the cell. Protein conformational issues are particularly important in neurodegeneration, as has been shown by misfolded protein forming the basis of plaques in Alzheimer's disease and prion diseases. This article focuses on protein structure/function specifically for proteins important in the pathogenesis of neurodegenerative conditions and those involved in apoptosis. The proteins used as examples in this review include alpha-synuclein, the promyelocytic leukemia protein, and glyceraldehyde 3-phosphate dehydrogenase.

Bennett, P. and D. J. Nicholl (1998). "Absence of the G209A mutation in the alpha-synuclein gene in British families with Parkinson's disease." Neurology 50(4): 1183.

Bajaj, N. P., C. Shaw, et al. (1998). "The genetics of Parkinson's disease and parkinsonian syndromes." J Neurol 245(10): 625-33.
The finding of a mutation in the alpha-synuclein gene in a rare autosomal dominant form of idiopathic Parkinson's disease (IPD), has prompted increased interest in identifying genes that account for the more common sporadic form. A number of association studies have suggested that functional polymorphisms in genes that play a role in dopamine, drug and toxin metabolism may increase the relative risk of IPD. Unfortunately, patient numbers are often small, and the results have not been consistently reproduced. This article reviews the evidence from epidemiological, imaging and genetic studies to determine the role of genetic susceptibility in IPD and parkinsonian syndromes.

Baba, M., S. Nakajo, et al. (1998). "Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies." Am J Pathol 152(4): 879-84.
Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, a point mutation in the gene encoding the presynaptic alpha-synuclein protein was identified in some autosomal-dominantly inherited familial PD pedigrees, and light microscopic studies demonstrated alpha-synuclein immunoreactivity in LBs of sporadic PD and DLB. To characterize alpha-synuclein in LBs, we raised monoclonal antibodies (MAbs) to LBs purified from DLB brains and obtained a MAb specific for alpha-synuclein that intensely labeled LBs. Light and electron microscopic immunocytochemical studies performed with this MAb as well as other antibodies to alpha-and beta-synuclein showed that alpha-synuclein, but not beta-synuclein, is a component of LBs in sporadic PD and DLB. Western blot analyses of highly purified LBs from DLB brains showed that full-length as well as partially truncated and insoluble aggregates of alpha-synuclein are deposited in LBs. Thus, these data strongly implicate alpha-synuclein in the formation of LBs and the selective degeneration of neurons in sporadic PD and DLB.

Arima, K., K. Ueda, et al. (1998). "NACP/alpha-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy." Acta Neuropathol (Berl) 96(5): 439-44.
We examined neuronal cytoplasmic inclusions (NCIs) and oligodendrocytic glial cytoplasmic inclusions (GCIs) in the pontine nuclei in multiple system atrophy (MSA) using antibodies against the non-amyloid beta component of Alzheimer's disease amyloid precursor protein (NACP/alpha-synuclein). Our immunohistochemical study revealed that anti-NACP antibodies labeled both NCIs and GCIs. Immunoelectron microscopy showed that positive reaction products were localized on the 15- to 30-nm-thick filamentous components of NCIs and GCIs. The present study demonstrates that NACP is associated with cytoplasmic inclusions of MSA, and suggests a role of NACP in abnormal filament aggregation in neuronal degeneration.

Arima, K., K. Ueda, et al. (1998). "Immunoelectron-microscopic demonstration of NACP/alpha-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson's disease and in dementia with Lewy bodies." Brain Res 808(1): 93-100.
We examined brains from Parkinson's disease and from dementia with Lewy bodies (LBs) by using antibodies to NACP/alpha-synuclein. Immunohistochemically, all of the antibodies against the amino-terminal region, NAC domain, and carboxyl-terminal region of NACP labeled not only LBs, pale bodies (PBs), and dystrophic neurites, but also fine thread-like structures in the neuronal perikarya (perikaryal threads) in the hypothalamus and brainstem nuclei. On electron microscopy, immunoreactive products were found to label the 9 to 12 nm-thick filamentous component (LB-filaments) of LBs, PBs, and perikaryal threads. The NACP-immunoreactive perikaryal threads, consisting of small bundles of LB-filaments and randomly oriented LB-filaments, presumably represent an initial stage of LB- or PB-formation. The present study indicates that the entire molecule of NACP is involved in the neuronal filament-aggregating processes of LB disorders.

Arawaka, S., Y. Saito, et al. (1998). "Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein." Neurology 51(3): 887-9.
In familial PD, a mutation of the alpha-synuclein gene has been identified. Alpha-synuclein also was revealed in Lewy bodies in idiopathic PD. Lewy bodies in neurodegeneration with brain iron accumulation type 1 (NBIA 1; Hallervorden-Spatz syndrome) were found to show immunostaining for alpha-synuclein/precursor of non-A beta component of Alzheimer's disease amyloid, indicating that alpha-synuclein is commonly associated with the formation of Lewy bodies in other sporadic and familial neurodegenerative diseases apart from PD.

(1998). "alpha-Synuclein gene and Parkinson's disease. The French Parkinson's Disease Study Group." Science 279(5354): 1116-7.