Ilani, T., D. Ben-Shachar, et al. (2001). "A peripheral marker
for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood
lymphocytes." Proc Natl Acad Sci U S A 98(2): 625-8.
Dopamine is a major neurotransmitter in the central nervous system, and its
receptors are associated with a number of neuropathological disorders such as
Parkinson's disease and schizophrenia. Although the precise pathophysiology of
schizophrenia remains unknown, the dopaminergic hypothesis of the illness
assumes that the illness results from excessive activity at dopamine synapses in
the brain. Because, at present, the diagnosis of schizophrenia relies on
descriptive behavioral and symptomatic information, a peripheral measurable
marker may enable a simpler, more rapid, and more accurate diagnosis and
monitoring. In recent years, human peripheral blood lymphocytes have been found
to express several dopamine receptors (D(3), D(4), and D(5)) by using molecular
biology techniques and binding assays. It has been suggested that these dopamine
receptors found on lymphocytes may reflect receptors found in the brain. Here we
demonstrate a correlation between the D(3) dopamine receptor on lymphocytes and
schizophrenia and show a significant elevation of at least 2-fold in the mRNA
level of the D(3), but not of the D(4), dopamine receptor in schizophrenic
patients. This increase is not affected by different antipsychotic drug
treatments (typical or atypical). Moreover, nonmedicated patients exhibit the
same pattern, indicating that this change is not a result of medical treatment.
We propose the D(3) receptor mRNA on blood lymphocytes as a marker for
identification and followup of schizophrenia.
Ingelson, M., S. F. Fabre, et al. (2001). "Increased risk for frontotemporal
dementia through interaction between tau polymorphisms and apolipoprotein E
epsilon4." Neuroreport 12(5): 905-9.
The tau gene has an important role in frontotemporal dementia (FTD) as
pathogenic mutations have been found in hereditary forms of the disease.
Furthermore, a certain extended tau haplotype has been shown to increase the
risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's
disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele,
Alzheimer's disease. By microsatellite analysis we investigated an intronic tau
polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD
patients (n = 36) and healthy controls (n = 39). No association between any of
the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE
epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose
that this extended tau haplotype in combination with apoE epsilon4 is a genetic
risk factor for FTD.
Iravani, M. M., S. Costa, et al. (2001). "GDNF reverses priming for dyskinesia
in MPTP-treated, L-DOPA-primed common marmosets." Eur J Neurosci 13(3):
597-608.
Parkinson's disease (PD) is associated with a progressive loss of dopamine
neurons in the substantia nigra and degeneration of dopaminergic terminals in
the striatum. Although L-DOPA treatment provides the most effective symptomatic
relief for PD it does not prevent the progression of the disease, and its
long-term use is associated with the onset of dyskinesia. In rodent and primate
studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA-
or MPTP-induced nigral degeneration and so may be beneficial in the treatment of
PD. In this study, we investigate the effects of GDNF on the expression of
dyskinesia in L-DOPA-primed MPTP-treated common marmosets, exhibiting dyskinesia.
GDNF or saline was administered by two intraventricular injections, 4 weeks
apart, to MPTP-treated, L-DOPA-treated common marmosets primed to exhibit
dyskinesia. Prior to GDNF or saline administration, all animals displayed marked
dyskinesia when treated with L-DOPA. GDNF administration produced a significant
improvement in motor disability and, following the second injection of GDNF, a
significant improvement in the locomotor activity was observed. Following the
administration of L-DOPA there was a greater reversal of disability and a
reduction in the intensity of L-DOPA-induced dyskinesia in GDNF-treated animals
compared to saline-treated controls. However, there was no significant
difference in L-DOPA's ability to increase locomotor activity between GDNF-treated
and saline-treated animals. GDNF treatment caused a significant increase in the
number of tyrosine hydroxylase-positive neurons in the substantia nigra, but no
change in [(3)H]mazindol binding to dopamine terminals was found in the striatum
of GDNF-treated animals compared to saline-treated controls. In GDNF-treated
animals a small but significant reduction in enkephalin mRNA was observed in the
caudate nucleus but not in the putamen or the nucleus accumbens. Substance P
mRNA expression was equally reduced in the caudate nucleus and the putamen of
the GDNF-treated animals but not in the nucleus accumbens. Intraventricular
administration of GDNF improved MPTP-induced disability and reversed dopamine
cell loss in the substantia nigra. GDNF also diminished L-DOPA-induced
dyskinesia, which may relate to its ability to partly restore nigral
dopaminergic transmission or to modify the activity of striatal output pathways.
Iwahashi, J., K. Tsuji, et al. (2001). "Isolation of amantadine-resistant
influenza a viruses (H3N2) from patients following administration of amantadine
in Japan." J Clin Microbiol 39(4): 1652-3.
In Japan, the use of amantadine for treatment of influenza A virus infection was
not accepted until November 1998, although it was widely used for treatment of
Parkinsonism. Since then, we have monitored the emergence of amantadine-resistant
viruses and isolated two viruses from patients on long-term treatment with
amantadine.
Iwata, A., S. Miura, et al. (2001). "alpha-Synuclein forms a complex with
transcription factor Elk-1." J Neurochem 77(1): 239-52.
alpha-Synuclein has been identified as a component of Lewy bodies in Parkinson's
disease and diffuse Lewy body disease, and glial cytoplasmic inclusions (GCIs)
in multiple system atrophy (MSA). To explore the role of alpha-synuclein in the
pathogenesis, we searched for molecules interacting with alpha-synuclein and
discovered that GCIs are stained by anti-Elk-1 antibody. To seek the role of
Elk-1 in synucleinopathies, we cotransfected alpha-synuclein and Elk-1 to
cultured cells, and found small granular structure complexes where the two
molecules colocalized. Moreover, alpha-synuclein and Elk-1 were co-immunoprecipitated
from the cell lysates. For formation of the complex, the presence of both ETS
and B-box domains of Elk-1 was required. Although there was no evidence of
direct binding between alpha-synuclein and Elk-1, we discovered that alpha-synuclein
and Elk-1 both bind to ERK-2, a MAP kinase. The effect of alpha-synuclein on the
MAP kinase pathway was assessed using the Pathdetect system, which showed
prominent attenuation of Elk-1 phosphorylation with alpha-synuclein, and
especially A53T mutant. Our results suggest that alpha-synuclein reacts with the
MAP kinase pathway, which might cause dysfunction of neurons and
oligodendrocytes and lead to neurodegeneration in Parkinson's disease and MSA.
Iwata, S. I., M. Nomoto, et al. (2001). "Regulation of GAP-43 protein and mRNA
in nigrostriatal dopaminergic neurons after the partial destruction of
dopaminergic terminals with intrastriatal 6-hydroxydopamine." Synapse
39(1): 16-22.
Changes in the level of GAP-43 and its mRNA in nigrostriatal dopaminergic
neurons in an animal model of the presymptomatic period of Parkinson's disease
were measured to find the characteristic features of GAP-43 in nigrostriatal
dopaminergic neurons. Since the dopaminergic neurons possess a relatively large
amount of GAP-43 protein and mRNA, the dopaminergic neurons must be endowed with
specific functions related to those of GAP-43. In this study, dopaminergic axon
terminals were partially destroyed by intrastriatal 6-hydroxydopamine (6-OHDA).
Rats were decapitated 3, 14, and 56 days following treatment. Levels of GAP-43
and tyrosine hydroxylase (TH) in the striatum were detected by immunoblotting
and quantified. The number of GAP-43 mRNA-positive neurons and that of TH
mRNA-positive neurons in the substantia nigra pars compacta (SNc) were detected
by in situ hybridization using alkaline phosphatase (ALP)-labeled probes. Levels
of GAP-43 in the striatum showed no significant alteration during the period of
the experiment, although levels of TH were gradually restored. The number of
GAP-43 mRNA-positive neurons as well as that of TH mRNA-positive neurons in the
SNc decreased. These results suggests that dopaminergic neurons restore their
axon terminals with little change in GAP-43, and that transcription and/or
stability of GAP-43 mRNA in the dopaminergic neurons are susceptible to the
toxin, although the dopaminergic neurons can maintain the translational product
in the terminals. This feature may be related with a degeneration of
dopaminergic neurons in Parkinson's disease.
Izumi, Y., H. Morino, et al. (2001). "Genetic studies in Parkinson's disease
with an alpha-synuclein/NACP gene polymorphism in Japan." Neurosci Lett
300(2): 125-7.
Dinucleotide repeat polymorphism has been observed in the promoter of the alpha-synuclein
(alpha-SYN)/NAC precursor protein (NACP) gene. Alpha-SYN/NACP allele 3
(described by Xia et al. (Ann. Neurol., 40 (1996) 207), equivalent to allele 1
described by Kruger et al. (Ann. Neurol. 45 (1999) 611) is reported to be
significantly more frequent among patients with sporadic Parkinson's disease (sPD)
than controls. In this study, we genotyped the same alpha-SYN/NACP polymorphism
in Japanese sPD patients and healthy controls, but found that any aliele showed
no significant difference between the two groups.