Kang, U. J., W. Y. Lee, et al. (2001). "Gene therapy for
Parkinson's disease: determining the genes necessary for optimal dopamine
replacement in rat models." Hum Cell 14(1): 39-48.
This article reviews the mechanism of dopamine delivery in the CNS in order to
determine the optimal set of genes for effective gene therapy in Parkinson's
disease (PD). Systematic neurobiological investigation of the biochemical steps
has revealed that tyrosine hydroxylase (TH), which has been used in earlier
studies, functions only when the essential cofactor, tetrahydrobiopterin (BH1)
is present. Transduction of the gene for GTP cyclohydrolase I, the first and
rate-limiting step in BH1 synthesis, along with the TH gene, generated cells
that are capable of producing L-DOPA spontaneously both in vitro and in vivo.
When the aromatic L-amino acid decarboxylase (AADC) gene was added as a third
gene, in an attempt to increase the conversion of L-DOPA to dopamine, feedback
inhibition by the end product, dopamine, on TH activity resulted. To circumvent
this problem, we employed a complementary strategy. Gene transfer of the
vesicular monoamine transporter was combined with AADC and produced genetically
modified cells that can convert L-DOPA to dopamine and store it for gradual
release. This approach provided a means to regulate final dopamine delivery by
controlling precursor doses and to achieve more sustained delivery of dopamine.
Our investigation into determining the genes necessary for optimal dopamine
delivery has been facilitated by in vivo biochemical assays using microdialysis.
This technique has provided us with a clear and quantitative tool to compare the
effects of various genes involved in dopamine synthesis and processing.
Kawamata, H., P. J. McLean, et al. (2001). "Interaction of alpha-synuclein and
synphilin-1: effect of Parkinson's disease-associated mutations." J Neurochem
77(3): 929-34.
alpha-Synuclein is a major component of Lewy bodies, a neuropathological feature
of Parkinson's disease. Two alpha-synuclein mutations, Ala53Thr and Ala30Pro,
are associated with early onset, familial forms of the disease. Recently,
synphilin-1, a protein found to interact with alpha-synuclein by yeast two
hybrid techniques, was detected in Lewy bodies. In this study we report the
interaction of alpha-synuclein and synphilin-1 in human neuroglioma cells using
a sensitive fluorescence resonance energy transfer technique. We demonstrate
that the C-terminus of alpha-synuclein is closely associated with the C-terminus
of synphilin-1. A weak interaction occurs between the N-terminus of alpha-synuclein
and synphilin-1. The familial Parkinson's disease associated mutations of alpha-synuclein
(Ala53Thr and Ala30Pro) also demonstrate a strong interaction between their
C-terminal regions and synphilin-1. However, compared with wild-type alpha-synuclein,
significantly less energy transfer occurs between the C-terminus of Ala53Thr
alpha-synuclein and synphilin-1, suggesting that the Ala53Thr mutation alters
the conformation of alpha-synuclein in relation to synphilin-1.
Khan, N., E. Graham, et al. (2001). "Parkinson's disease is not associated with
the combined alpha-synuclein/apolipoprotein E susceptibility genotype." Ann
Neurol 49(5): 665-8.
A recent study showed significant association of sporadic Parkinson's disease
with a polymorphism within the alpha-synuclein gene and closely linked DNA
markers on chromosome 4q and the APOE epsilon4 allele. A combined alpha-synuclein/APOE-epsilon4
genotype increased the relative risk of developing Parkinson's disease 12-fold.
We failed to confirm this association in a much larger sample of
histopathologically proven cases of Parkinson's disease and controls.
Kimura, M., S. Matsushita, et al. (2001). "No evidence of association between a
dopamine transporter gene polymorphism (1215A/G) and Parkinson's disease."
Ann Neurol 49(2): 276-7.
Kirik, D., C. Winkler, et al. (2001). "Growth and functional efficacy of
intrastriatal nigral transplants depend on the extent of nigrostriatal
degeneration." J Neurosci 21(8): 2889-96.
Previous studies have shown that the functional efficacy of intrastriatal
transplants of fetal dopamine (DA) neurons in the rat Parkinson model depends on
their ability to establish a new functional innervation of the denervated
striatum. Here we report that the survival, growth, and function of the grafted
DA neurons greatly depend on the severity of the lesion of the host
nigrostriatal system. Fiber outgrowth, and to a lesser extent also cell
survival, were significantly reduced in animals in which part of the intrinsic
DA system was left intact. Moreover, graft-induced functional recovery, as
assessed in the stepping, paw-use, and apomorphine rotation tests, was obtained
only in severely lesioned animals, i.e., in rats with >70% DA denervation of the
host striatum. Functional recovery seen in these animals in which the
6-hydroxydopamine (6-OHDA) lesion was confined to the striatum was more
pronounced than that previously obtained in rats with complete lesions of the
mesencephalic DA system, indicating that spared portions of the host DA system,
particularly those innervating nonstriatal forebrain areas, may be necessary for
the grafts to exert their optimal functional effect. These data have
implications for the optimal use of fetal nigral transplants in Parkinson
patients in different stages of the disease.
Klein, C. (2001). "[The genetics of Parkinson syndrome]." Schweiz Rundsch Med
Prax 90(23): 1015-23.
A genetic contribution to the etiology of Parkinson's disease was first
suspected by Charcot and later confirmed by case control, family, and twin
studies, as well as by the description of large parkinsonian families with
Mendelian inheritance of the disease. Recent progress in the field of molecular
neurogenetics has led to the identification of several Parkinson disease genes
and gene loci. Mutations in the alpha-Synuclein gene (PARK1) and in the gene for
the ubiquitin C-terminal hydrolase I (PARK5), along with two gene loci harboring
currently unknown genes (PARK3 and PARK4), have been linked to very rare
autosomal dominantly inherited parkinsonian syndromes. Mutations in the parkins
gene (PARK2), causing autosomal recessive early-onset parkinsonism, are much
more common and therefore of clinical relevance. A second gene locus for an
autosomal dominantly inherited Parkinsonian syndrome was recently localized on
chromosome 1 (PARK6). All three parkinson genes identified thus far imply the
involvement of the ubiquitin pathway of protein degradation in the pathogenesis
of Parkinson's disease.
Kluger, J. (2001). "Parkinson's disease. Lubricating gummed-up brains." Time
157(2): 86, 89.
Kuhn, W., T. Hummel, et al. (2001). "Plasma homocysteine and MTHFR C677T
genotype in levodopa-treated patients with PD." Neurology 56(2):
281; discussion 281-2.
Kuopio, A., R. J. Marttila, et al. (2001). "Familial occurrence of Parkinson's
disease in a community-based case-control study." 7(4): 297-303.
Purpose: To study the occurrence of Parkinson's disease (PD) in the relatives of
parkinsonian patients (n=119), and of their matched controls (n=238).Scope: More
patients reported a positive family history of PD in their first degree
relatives, compared to their controls (OR 2.7, 95% CI 1.3-5.9), and the
incidence of PD among those relatives was also significantly higher (OR 1.4, 95%
CI 1.1-1.8).Conclusions: Familial occurrence of PD is not necessarily a sign of
genetic mechanisms in the etiology of PD. Shared environment with common risk
factors might be even more important.