Miho Murata

Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease.

To identify susceptibility variants for Parkinsons disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 × 10−12) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 × 10−9). We also detected strong associations at SNCA on 4q22 (P = 7.35 × 10−17) and LRRK2 on 12q12 (P = 2.72 × 10−8), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

Clinical heterogeneity of α-synuclein gene duplication in Parkinson's disease

Recently, genomic multiplications of α‐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 Parkinsons disease (ADPD).

Association studies of multiple candidate genes for Parkinson's disease using single nucleotide polymorphisms

We studied 20 single nucleotide polymorphisms in 18 candidate genes for association with Parkinsons disease. We found that homozygosity for the V66M polymorphism of the brain‐derived neurotrophic factor (BDNF) gene occurs more frequently in patients with Parkinsons disease than in unaffected controls (χ2 = 5.46) and confirmed an association with the S18Y polymorphism of the UCH‐L1 gene. Our results provide genetic evidence supporting a role for BDNF in the pathogenesis of Parkinsons disease.

Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA

Huntingtons disease (HD) is an autosomal dominant inheritable neurodegenerative disorder currently without effective treatment. It is caused by an expanded polyglutamine (poly Q) tract in the corresponding protein, huntingtin (htt), and therefore suppressing the huntingtin expression in brain neurons is expected to delay the onset and mitigate the severity of the disease. Here, we have used small interfering RNAs (siRNAs) directed against the huntingtin gene to repress the transgenic mutant huntingtin expression in an HD mouse model, R6/2. Results showed that intraventricular injection of siRNAs at an early postnatal period inhibited transgenic huntingtin expression in brain neurons and induced a decrease in the numbers and sizes of intranuclear inclusions in striatal neurons. Treatments using this siRNA significantly prolonged model mice longevity, improved motor function and slowed down the loss of body weight. This work suggests that siRNA-based therapy is promising as a future treatment for HD.

Mutations for Gaucher Disease Confer High Susceptibility to Parkinson Disease

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.

Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study.

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 Parkinsons 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.

β-Synuclein gene alterations in dementia with Lewy bodies

Objective: To determine whether mutations in the genes for α-synuclein or β-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 α-synuclein and β-synuclein, as α-synuclein alterations cause PD and β-synuclein may modulate α-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 β-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the β-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 β-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 α-synuclein aggregation without evidence of β-synuclein aggregation. Conclusion: Mutations in the β-synuclein gene may predispose to DLB.

Dopaminergic stimulation up-regulates the in vivo expression of brain-derived neurotrophic factor (BDNF) in the striatum

We investigated the effect of dopamine on the in vivo expression of brain‐derived neurotrophic factor (BDNF) in the striatum of mouse. BDNF mRNA expression in the striation, which was Quantified with the reverse transcriptase polymerase chain reaction, was up‐repulated from 2 h after oral administration of levodopa, a precursor of dopamine. The increase was sustained for 16 h. Co‐administrstion of haloperidol partially inhibited dopamine‐induced BDNF enhancement. These data suggest that dopaminergic stimulation directly promotes the expression of BDNF in the striatum in vivo.

Efficacy of the anti–IL-6 receptor antibody tocilizumab in neuromyelitis optica A pilot study

Objective: To evaluate the safety and efficacy of a humanized anti–interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO). Methods: Seven patients with anti–aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year. We evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue. Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells. Results: Six females and one male with NMO were enrolled. After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p < 0.005). The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly. The ameliorating effects on intractable pain exceeded expectations. Conclusion: Interleukin-6 receptor blockade is a promising therapeutic option for NMO. Classification of evidence: This study provides Class IV evidence that in patients with NMO, TCZ reduces relapse rate, neuropathic pain, and fatigue.

Zonisamide has beneficial effects on Parkinson's disease patients

Zonisamide (ZNS) is a generally well tolerated anticonvulsant that has beneficial effects on Parkinsons 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.