Elucidation of pathophysiology and development of treatment for spinocerebellar ataxia using a novel mouse model

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07503
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Yokohama City University
• Principal Investigator: DOI Hiroshi 横浜市立大学, 医学部, 准教授 (10326035)
• Co-Investigator(Kenkyū-buntansha): 竹内 英之 横浜市立大学, 医学部, 准教授 (30362213) ; 田中 章景 横浜市立大学, 医学研究科, 教授 (30378012) ; 國井 美紗子 横浜市立大学, 医学部, 助教 (80725200)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: spinocerebellar ataxia / mouse model / calcium channel

Outline of Final Research Achievements

Mouse model (Cacna1g_R1723H_KI) with the R1723H variant in Cacna1g corresponding to the R1715H variant of CACNA1G, which is responsible for spinocerebellar ataxia type 42 (SCA42), were developed by genome editing using CRISPR / Cas9. Behavioral analysis confirmed that both heterozygous and homozygous knock-in mice showed ataxia on the rotarod and footprint tests. Pathologically, degeneration of Purkinje cells (PCs) was observed at week 50 in both heterozygous and homozygous knock-in mice. Electrophysiological analysis of the PC revealed a positive shift in the current-voltage curve and a reduced frequency of rebound firing in homozygous knock-in mice. Therefore, we conclude that the SCA42 model has been established. Furthermore, oral administration of T-type VGCC modifier showed improvement in ataxia and PC neurodegeneration in heterozygous knock-in mice.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

SCA分野においては、現時点で有効な疾患修飾治療が存在しない。SCA42自体は希少疾患であるが、本研究ではSCA42の症状を再現するモデルの開発に成功し、チャネル機能修飾治療により失調症状、神経変性が抑制されることを示唆する所見が得た。この結果は、SCAの新たな疾患修飾治療の可能性を示したものと考えられる。