Parkinson Disease: Murata M

Miziuno Y, Okuma Y, Kikuchi S, Kuno S, Hashimoto T, Hasegawa K, Mano Y, Miwa H, Murata M, Yamamoto M, Yokochi F, Okiyama R, Kanazawa A, Shinpo K, Chuma T, Higashi T, Maruyama T, Mizuta E, Yamazaki S, Anonymous00188. · Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan · Rinsho Shinkeigaku. · Pubmed #12708433 No free full text.

This publication has no abstract.

Murata M. · Department of Neurology, National Center Hospital of Neurology & Psychiatry, 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8551, Japan. · Brain Nerve. · Pubmed #19378816 No free full text.

Abstract: In this paper, I have discussed a modification in the current treatment strategy for Parkinson disease (PD) and the application of a new drug, zonisamide, for the treatment of PD. At the beginning of the 21st century, the following views were held strongly regarding the treatment of PD (1) L-dopa may be toxic, (2) dopamine agonist may exert neuroprotective effects, (3) dopamine agonists should be used as the initial treatment for parkinsonian patients without dementia or psychosis. However, the paradigm has now been modified to state (1) L-dopa does not accelerate disease progression, (2) no treatment modality exerts neuroprotective effects, (3) L-dopa is more effective than dopamine agonists in alleviating motor symptoms and improving the activities of daily living (ADL) score, in parkinsonian patients. Treatment with dopamine agonist is associated with fewer motor complications than L-dopa. Dopamine agonist therapy is associated with more frequent adverse events than L-dopa therapy, such as hallucinations and somnolence. There is no evidence of a long-term benefit with initial dopamine agonist therapy. Therefore, the treatment should be determined on a case-by-case basis. Furthermore, some clinical trials have indicated that early dopaminergic support for the degenerating dopaminergic system offers significant long-term clinical benefits for parkinsoninan patients. Zonisamide (25-50mg/day) improves motor functions and wearing-off without worsening dyskinesia in advanced cases of Parkinson disease. Furthermore, zonisamide affects an increases in the levels of glutathione and manganese superoxide dismutase expression and, it ameliorates reduction in the number of dopaminergic neurons in mice treated with 6hydroxydopamine (6-OHDA). Zonisamide may exert neuroprotective effects in parkinsonian patients.

Murata M. · Department of Neurology, National Center Hospital of Neurology & Psychiatry. · Rinsho Shinkeigaku. · Pubmed #19198140 No free full text.

Abstract: The prognosis of Parkinson's disease (PD) has been improved with developing anti-parkinsonian agents. Recently the re-evaluation of L-dopa and dopamine agonists is the topic in the world based on focusing non motor side effects of dopamine agonists such as sudden uncontrollable somnolence and valvulopathy in place of motor complication. The development of anti-parkinsonian drugs based on the new mechanism has been progressed such as CEP-1347, AAV-neuturin, AAV-GAD, and AAV-DDC. The most reliable new drug is zonisamide which is originally synthesized in Japan for epilepsy. A nation-wide randomized double blind study showed that Zonisamide improves motor function of advanced PD patients. Long-term efficacy was also shown. The mechanism of zonisamide for PD is the increase of dopamine synthesis and moderate inhibition of monoamine oxydase B activity. Inhibitatory effects of sodium channel and T-type calcium channel may also affects. Zonisamide has neuroprotective effects though inhibition of quinoprotein and increasing the levels of GSH and Mn SOD. Up to now we have no agents with clinically evidenced neuroprotective effects for PD. Base on the results of ELLDOPA study and "delayed start" clinical trials the most important concept for neuroprotection may be the early dopaminergic support for the degenerating dopaminergic system.

Murata M. · Department of Neurology, National Center Hospital of Neurology & Psychiatry, Kodaira, Japan. · Parkinsonism Relat Disord. · Pubmed #19131036 No free full text.

Abstract: l-dopa has many advantages as initial therapy for Parkinson's disease (PD). It is safer, more efficacious, associated with fewer adverse effects, few interactions, easier for patients to use and for clinicians to prescribe, and cheaper than dopamine (DA) agonists. Although l-dopa is more likely than DA agonists to introduce motor fluctuations and dyskinesia, l-dopa is also more effective in improving motor function. Furthermore, there is no long-term benefit from delaying l-dopa based on the risk of motor complications or psychiatric symptoms. Many investigations have shown that l-dopa does not accelerate disease progression. Now is the time to re-evaluate l-dopa for initial treatment of PD.

Murata M. · No affiliation provided · Nippon Yakurigaku Zasshi. · Pubmed #18408339 No free full text.

This publication has no abstract.

Murata M. · Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry. · Nippon Rinsho. · Pubmed #15462390 No free full text.

Abstract: Wearing-off, predictable end of dose deterioration, is one of the major problems of long-term levodopa treatment for Parkinson's disease. The mechanisms of wearing-off are (1) loss of striatal dopamine storage, (2) change in the peripheral pharmacokinetics of levodopa and (3) modification of dopamine receptors. The main therapeutic strategy for wearing-off is continuous stimulation of dopamine system. For this purpose, we increase frequency of levodopa doses and use long half-life dopamine agonist(continuous stimulation of dopamine receptors), COMT inhibitor and MAOB inhibitor (prolongation of the half-life of levodopa and dopamine), and zonisamide (long-term increase of dopamine synthesis).

Murata M. · Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. · Curr Pharm Des. · Pubmed #14965331 No free full text.

Abstract: We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically. An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off. Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years. Nation-wide double-blind controlled study confirmed that the small dose (50mg/day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein. ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system. Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca(++) channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

Murata M. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #13677891 No free full text.

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Ikebe S, Harada T, Hashimoto T, Kanazawa I, Kuno S, Mizuno Y, Mizuta E, Murata M, Nagatsu T, Nakamura S, Takubo H, Yanagisawa N, Narabayashi H. · Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan. · Parkinsonism Relat Disord. · Pubmed #12735915 No free full text.

Abstract: We report a consensus statement of the collaborative research group on the prevention and treatment of malignant syndrome (MS) in Parkinson's disease. The syndrome is quite similar to neuroleptic MS. Although sudden withdrawal of levodopa was the most frequent cause, many other precipitating events were found such as intercurrent infections, dehydration, hot weather, discontinuation of other anti-parkinsonian drugs, and "wearing off" phenomenon.Awareness of this syndrome is most important for its early detection and the prompt commencement of treatment. MS should be suspected whenever the body temperature rises above 38 degrees C without an apparent cause. Treatment consists of ample intravenous fluid, cooling the body, anti-parkinsonian drugs (particularly levodopa and bromocriptine), dantrolene sodium, and antibiotics if infection is present. Rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure constitute serious complications.

Momose Y, Murata M, Kanazawa I. · Department of Neurology, Graduate School of Medicine, University of Tokyo. · Nippon Rinsho. · Pubmed #11068447 No free full text.

Abstract: After the advent of levodopa, treatment of Parkinson's disease has changed and the activity of daily life of patients has been remarkably improved; whereas, many patients experience various problems such as wearing-off, dyskinesia, dystonia, neuropsychiatric problems, and dysautonomia. Especially, wearing-off and dyskinesia emerge with the change of absorptional pattern of levodopa and could be solved by regulating the timing and the dose of it. Recently, some new drugs for Parkinson's disease have been available and we physician have a wide choice of them. It is important to make a careful choice of and manipulate of doses of drugs after understanding daily life of each patient enough.

Ohno K, Miyazawa S, Hashiguchi M, Unemoto T, Itoh A, Echizen H, Rikihisa T, Ogata H, Murata M. · Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Japan. · Yakugaku Zasshi. · Pubmed #14577334 links to  free full text

Abstract: OBJECTIVE: Drug-induced extrapyramidal symptoms (DIEPS) often substantially compromise quality of life (QOL) of patients receiving drugs with central antidopaminergic activities. A lack of comprehensive screening method based upon patients' subjective symptoms for detecting DIEPS appears to have prevented pharmacists from delivering satisfactory pharmaceutical care for these patients. Thus, we have attempted to develop a comprehensive questionnaire for screening patients having higher risks of developing DIEPS. METHODS: One hundred fourteen outpatients taking gastroprokinetic drugs (itopride, cisapride, trimebutine, domperidone and metoclopramide) at least 2 weeks participated in the study. One patient with familial Parkinson disease served as a positive reference. They undertook a questionnaire consisting of 9 comprehensive questions written in non-technical words that were aimed to detect typical symptoms of Parkinsonism including akathisia and dyskinesia. Each symptom was scored in a semiquantitative scale [i.e., from 1 (not at all) to 5 (very much)] by the patients. RESULTS: Of the 108 subjects who successfully completed the questionnaires, 43 gave scores 2 or greater indicating the presence of DIEPS. However, no statistically significant correlations were observed between the scores of any possible pairs of the questionnaire items. Five subjects had a mean questionnaire score of equal to or greater than 1.6, and the patient with familiar Parkinsonism had the highest mean score of 1.9. CONCLUSION: The questionnaire presented herein detected 4 patients with suspected DIEPS. Further studies should be warranted to assess whether it would be useful for pharmacists as a screening tool for DIEPS in patients having higher risks of DIEPS.

Murata M, Horiuchi E, Kanazawa I. · Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. · Neurosci Res. · Pubmed #11755227 No free full text.

Abstract: Zonisamide (ZNS) is a generally well tolerated anticonvulsant that has beneficial effects on Parkinson's disease (PD). ZNS (300 mg/day) given to a patient with PD who incidentally had convulsive attacks, ameliorated the attacks and, surprisingly, his parkinsonian symptoms. We, therefore, carried out an open trial of ZNS on nine patients with PD. Patients were given 50-200 mg/day ZNS in addition to their anti-PD drugs. Seven clearly showed lessening of symptoms, especially wearing-off. We speculate that long lasting activation of dopamine synthesis by ZNS ameliorates parkinsonian symptoms, in particular wearing-off.

Torizuka K, Mizuno Y, Kubo A, Konishi J, Yonekura Y, Hatazawa J, Momose T, Murata M, Amano T, Fukuyama H, Kuwabara Y. · Kyoto University. · Kaku Igaku. · Pubmed #10586546 No free full text.

Abstract: A Phase 2 multicenter trial of 123I-IBF, (S)-5-iodo-7-N-[(1-ethyl-2- pyrrolidinyl)methyl]carboxamido-2,3-dihydrobenzofuran, was conducted to evaluate its clinical efficacy and safety in 158 patients with Parkinson's disease (PD) or Parkinson syndromes (PS). SPECT data were acquired at two hours (2H-SPECT), after intravenous injection of 123I-IBF (167 MBq). Additional SPECT scan at three hours (3H-SPECT) and dynamic SPECT scan at most until one hour were performed when possible. No severe side effects due to 123I-IBF injection were observed. The sensitivity, specificity and accuracy for discriminating PS from PD using the striatal specific binding count-to-frontal cortex count ratio (St/Fc-1) in 3H-SPECT were 72.7%, 81.0% and 78.1% in 64 clinically definite cases (i.e., typical cases), respectively. The putamen-to-caudate ratios were significantly lower in striatonigral degeneration compared with those in PD. The contralateral-to-ipsilateral ratios against the symptomatic side of tremor and/or rigidity in the patients with PD (Hoehn & Yahr I) were significantly higher than the left-to-right ratios in the normal controls. St/Fc-1 in 3H-SPECT was significantly lower in the patients showing a poor response to levodopa than in those showing a good response. The dopamine D2 receptor binding potential (k3/k4), obtained by dynamic SPECT based on compartment model analysis, correlated well with the striatal specific binding count-to-occipital cortex count ratio. These results suggest that 123I-IBF is a promising agent for differential diagnosis and pathophysiological evaluation of PD and PS.

Mitsui J, Mizuta I, Toyoda A, Ashida R, Takahashi Y, Goto J, Fukuda Y, Date H, Iwata A, Yamamoto M, Hattori N, Murata M, Toda T, Tsuji S. · Department of Neurology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan. · Arch Neurol. · Pubmed #19433656 No free full text.

Abstract: BACKGROUND: Increased frequency of pathogenic variants in GBA, the causative gene for Gaucher disease, has been suggested to be associated with Parkinson disease (PD). OBJECTIVES: To conduct comprehensive resequencing of GBA to identify all sequence variants and to investigate the association of these variants with PD. DESIGN: Case-control study. SETTING: Multicenter university-based study. PARTICIPANTS: Five hundred thirty-four patients with PD, 34 families in which multiple patients with PD are present, and 544 control subjects. MAIN OUTCOME MEASURES: Disease status and GBA variations. RESULTS: Comprehensive resequencing of GBA in 534 patients with PD and 544 controls revealed 27 sequence variants: 11 pathogenic variants associated with Gaucher disease, 11 nonsynonymous variants not associated with Gaucher disease, and 5 synonymous variants. Fifty patients with PD (9.4%) had 1 of the 11 pathogenic variants in the heterozygous state, whereas only 2 controls (0.37%) had such variants (odds ratio, 28.0). Among the pathogenic variants, R120W and L444P/RecNciI were highly prevalent, and each showed a significant association with PD. Furthermore, other rare pathogenic variants were found in 13 patients with PD but not in the controls, further confirming the role of these rare variants in the susceptibility to PD. Patients with PD carrying pathogenic variants were significantly younger than those not carrying them. In addition, concordance of PD states and pathogenic variants was observed in 8 multiplex families with PD. CONCLUSION: Heterozygous pathogenic variants in GBA confer a high risk for sporadic PD, even for familial clustering, and are associated with significantly earlier age at onset of disease.

Tomiyama H, Mizuta I, Li Y, Funayama M, Yoshino H, Li L, Murata M, Yamamoto M, Kubo S, Mizuno Y, Toda T, Hattori N. · Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. · J Hum Genet. · Pubmed #18923807 No free full text.

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology with probable involvement of genetic-environmental factors. The majority of PD cases (approximately 90-95%) are sporadic, while familial cases account for approximately 5-10% of PD. In a recent report, a heterozygous LRRK2 P755L mutation within LRRK2 exon 19 was found in 2% of Chinese sporadic PD patients and in 0% of normal controls or Caucasians, suggesting that the mutation is disease-associated with ethnic specificity. To further evaluate the role of LRRK2 P755L variant in sporadic PD, we performed direct sequencing of LRRK2 exon 19 in 501 Japanese sporadic PD patients (male 249, female 252, aged 28-92 years, mean 65.0 years) and 583 controls of the Japanese general population as an extended association study. In this group, we found six patients (6/501 = 1.2%) and eight controls of the general population (8/583 = 1.6%) with a heterozygous P755L variant (P = 0.80, chi(2) = 0.064). No other variants were found in exon 19. Together with previous reports, our extended case-controlled study of large sample size suggests that LRRK2 P755L is a non-disease-associated polymorphism in PD patients.

Mizuta I, Tsunoda T, Satake W, Nakabayashi Y, Watanabe M, Takeda A, Hasegawa K, Nakashima K, Yamamoto M, Hattori N, Murata M, Toda T. · Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka, 565-0871, Japan. · Hum Genet. · Pubmed #18568448 No free full text.

Abstract: Parkinson's disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes identified alpha-synuclein (SNCA) as a susceptibility gene for sporadic PD (P = 1.7 x 10(-11)). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P = 0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes, but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P < 0.01; 882 cases and 938 control subjects). We replicated the association analysis for these SNPs in a second independent sample set (521 cases and 1,003 control subjects). One SNP, rs1805874 in calbindin 1 (CALB1), showed significance in both analyses (P = 7.1 x 10(-5); recessive model). When the analysis was stratified relative to the SNCA genotype, the odds ratio of CALB1 tended to increase according to the number of protective alleles in SNCA. In contrast, FGF20 was significant only in the subgroup of SNCA homozygote of risk allele. CALB1 is a calcium-binding protein that widely is expressed in neurons. A relative sparing of CALB1-positive dopaminergic neurons is observed in PD brains, compared with CALB1-negative neurons. Our genetic analysis suggests that CALB1 is associated with PD independently of SNCA, and that FGF20 is associated with PD synergistically with SNCA.

Asanuma M, Miyazaki I, Diaz-Corrales FJ, Miyoshi K, Ogawa N, Murata M. · Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Okayama 700-8558, Japan. · Neurosci Res. · Pubmed #18022268 No free full text.

Abstract: The neurotoxicity of dopamine (DA) quinones as dopaminergic neuron-specific oxidative stress is considered to play a role in the pathogenesis and/or progression of Parkinson's disease (PD), since DA quinones conjugate with several key PD pathogenic molecules (e.g., tyrosine hydroxylase, alpha-synuclein and parkin) to form protein-bound quinone (quinoprotein) and consequently inhibit their functions. Zonisamide (ZNS) is used as an anti-epileptic agent but also improved the cardinal symptoms of PD in recent clinical trials in Japan. To evaluate the effects of ZNS on excess cytosolic free DA-induced quinone toxicity, we examined changes in DA quinone-related indices after ZNS treatment both in in vitro cell-free system and in cultured cells. Co-incubation of DA and ZNS in a cell-free system caused conversion of DA to stable melanin via formation of DA-semiquinone radicals and DA chrome. Long-term (5 days) treatment with ZNS decreased quinoprotein and increased DA/DOPA chromes in dopaminergic CATH.a cells. ZNS significantly inhibited quinoprotein formation induced by treatment with tetrahydrobiopterin and ketanserin that elevate cytosolic free DA in the cells. Our results suggest that the novel anti-parkinsonian agent ZNS possesses preventing effects against DA quinone formation induced by excess amount of cytosolic DA outside the synaptic vesicles.

Satake W, Mizuta I, Suzuki S, Nakabayashi Y, Ito C, Watanabe M, Takeda A, Hasegawa K, Sakoda S, Yamamoto M, Hattori N, Murata M, Toda T. · Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan. · Neuroreport. · Pubmed #17515805 No free full text.

Abstract: A genetic association between the fibroblast growth factor 20 (FGF20) gene and Parkinson's disease has been found by the pedigree disequilibrium test. This association, however, was not replicated by a case-control association study. In order to clarify the association between the FGF20 gene and Parkinson's disease, we attempted to replicate this association by a case-control association study using a large number of Japanese samples (1388 patients and 1891 controls). rs1721100 exhibited a significant difference in allele C versus G (P=0.0089), and in genotype CC+CG versus GG (P=0.0053). Haplotype association analysis showed that haplotype 2 was the protective haplotype for Parkinson's disease (permutation-P=0.0075). These results suggest that the FGF20 gene is a susceptibility gene for Parkinson's disease in the Japanese population.

Funayama M, Li Y, Tomiyama H, Yoshino H, Imamichi Y, Yamamoto M, Murata M, Toda T, Mizuno Y, Hattori N. · Research Institute for Diseases of Old Age, Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, and Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu, Japan. · Neuroreport. · Pubmed #17314670 No free full text.

Abstract: To assess the effect of genetic factors on sporadic Parkinson disease, we performed a case-control study of a variant (G2385R) in Leucine-Rich Repeat kinase 2 among the Japanese population. The G2385R (c.7153G>A) variant was reported as a risk factor for sporadic Parkinson disease in the Chinese population from Taiwan and Singapore. Genotyping was conducted in 448 Parkinson disease patients and 457 healthy controls. The frequency of A allele in Parkinson disease was significantly higher than in the control (P=1.24x10(-4), odds ratio 2.63, 95% confidence interval 1.56-4.35). Our results suggest that the G2385R variant is a risk factor for sporadic Parkinson disease in the Asian population.

Murata M, Hasegawa K, Kanazawa I, Anonymous00826. · Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan. · Neurology. · Pubmed #17200492 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy, safety and tolerability of daily doses of 25, 50, and 100 mg of zonisamide (ZNS) administered as adjunctive treatment in patients with Parkinson disease (PD). METHODS: We conducted a multicenter, randomized, double-blind, parallel-treatment, placebo-controlled study in Japan. Patients with PD who showed insufficient response to levodopa treatment were given placebo for 2 weeks and then treated for 12 weeks with 25, 50, or 100 mg/day of ZNS or placebo, in addition to levodopa, followed by a 2-week dose-reduction period. The primary endpoint was change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III at the final assessment point. Secondary endpoints included changes from baseline in total daily "off" time; total scores of UPDRS Parts I, II, and IV; and Modified Hoehn and Yahr Scale score. Safety analysis was based on the incidence of adverse events. RESULTS: There was significant improvement in the primary endpoint in the 25-mg and 50-mg groups vs placebo. The duration of "off" time was significantly reduced in the 50-mg and 100-mg groups vs placebo. Dyskinesia was not increased in ZNS groups. The incidence of adverse effects was similar between the 25-mg, 50-mg, and placebo groups but higher in the 100-mg group. CONCLUSIONS: Zonisamide is safe, effective and well tolerated at 25 to 100 mg/day as an adjunctive treatment in patients with Parkinson disease.

Mizuta I, Satake W, Nakabayashi Y, Ito C, Suzuki S, Momose Y, Nagai Y, Oka A, Inoko H, Fukae J, Saito Y, Sawabe M, Murayama S, Yamamoto M, Hattori N, Murata M, Toda T. · Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan. · Hum Mol Genet. · Pubmed #16500997 links to  free full text

Abstract: Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case-control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case-control populations, we found that a SNP in alpha-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0 x 10(-10)). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D'>0.9) spanning approximately 120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0 x 10(-9)-1.7 x 10(-11)). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.

Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, Kitami T, Sato K, Kuroda R, Tomiyama H, Mizoguchi K, Murata M, Toda T, Imoto I, Inazawa J, Mizuno Y, Hattori N. · Department of Neurology, Juntendo University School of Medicine, Hongo, Tokyo, Japan. · Ann Neurol. · Pubmed #16358335 No free full text.

Abstract: OBJECTIVE: Recently, genomic multiplications of alpha-synuclein gene (SNCA) have been reported to cause hereditary early-onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinson's disease (ADPD). METHODS: We screened 113 ADPD probands and 200 sporadic PD cases by quantitative polymerase chain reaction and confirmed SNCA multiplications by fluorescence in situ hybridization (FISH) and comparative genomic hybridization array. RESULTS: Two families (two patients from Family A and one from Family B) with SNCA duplication were identified among ADPD patients. Even though they had the same SNCA duplication, one patient had dementia. Because there was exactly the same difference between the regions originated from each patient, the finding suggests that the phenotype of SNCA multiplication may be also influenced by the range of duplication region. We also detected asymptomatic carriers in the families of both patients. Interestingly, the penetrance ratio was 33.3% (2/6) in one kindred, indicating that the ratio was very much lower than expected. INTERPRETATION: These two newly identified Japanese patients with SNCA duplication and the five previously identified American and European families with SNCA triplication or duplication mutations indicate that the incidence of SNCA multiplication may be more frequent than previously estimated.

Yanagisawa N, Yamamoto M, Kikuchi S, Murata M, Ohkuma Y. · Kanto Rosai Hospital. · J Neurol. · Pubmed #15505751 No free full text.

This publication has no abstract.

Ohtake H, Limprasert P, Fan Y, Onodera O, Kakita A, Takahashi H, Bonner LT, Tsuang DW, Murray IV, Lee VM, Trojanowski JQ, Ishikawa A, Idezuka J, Murata M, Toda T, Bird TD, Leverenz JB, Tsuji S, La Spada AR. · Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan. · Neurology. · Pubmed #15365127 links to  free full text

Abstract: OBJECTIVE: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). METHODS: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. RESULTS: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. CONCLUSION: Mutations in the beta-synuclein gene may predispose to DLB.

Toda T, Momose Y, Murata M, Tamiya G, Yamamoto M, Hattori N, Inoko H. · Division of Functional Genomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, 565-0871, Osaka, Japan. · J Neurol. · Pubmed #14579123 No free full text.

Abstract: To identify susceptibility genes for Parkinson's disease (PD) and to establish tailor-made medicine for PD, we studied 20 single nucleotide polymorphisms (SNPs) in 18 candidate genes for association with PD. We found that homozygosity for the V66M polymorphism of the BDNF gene occurs more frequently in PD patients than in unaffected controls and confirmed an association with the S18Y polymorphism of the UCHL1 gene.We further started microsatellite marker-based genome-wide association studies by using the pooled DNA method. We have finished checking approximately 6800 markers and found some significant associations (p=3.9 x 10(-6)) on chromosome 1 where other studies showed a linkage. Genes in linkage disequilibrium with these markers may be associated with pathogenesis of PD.