Miho Murata

Bio: Miho Murata is an academic researcher from University of Tokyo. The author has contributed to research in topics: Parkinson's disease & Parkinsonism. The author has an hindex of 34, co-authored 115 publications receiving 5371 citations.

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

Abstract: To identify susceptibility variants for Parkinson's 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 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 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

Abstract: Objective 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 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 flurorescence 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. Ann Neurol 2006

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

Abstract: 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 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 improves motor function in Parkinson disease: A randomized, double-blind study

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 Parkinson9s 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.

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Network Medicine: A Network-Based Approach to Human Disease

Abstract: Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships among apparently distinct (patho)phenotypes. Advances in this direction are essential for identifying new disease genes, for uncovering the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing, and for identifying drug targets and biomarkers for complex diseases.

Genome-wide association study reveals genetic risk underlying Parkinson's disease

Abstract: We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding a-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action

Abstract: To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.