The relationship between spinocerebellar ataxia type 6 and microglial neuroinflammation

2015 Fiscal Year Final Research Report

• Project/Area Number: 26860661
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Aikawa Tomonori 東京医科歯科大学, 脳統合機能研究センター, 助教 (10597149)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 脊髄小脳失調症６型 / Cav2.1 / ポリグルタミン病 / プルキンエ細胞変性 / ミクログリア / Toll like receptor / MyD88 / neuroinflammation

Outline of Final Research Achievements

Spinocerebellar ataxia type 6 (SCA6) is dominantly inherited neurodegenerative disease, caused by CAG repeat expansion in the Cav2.1 calcium channel. Its key pathological features include selective cerebellar Purkinje cell (PC) loss. However, its molecular basis remains elusive. Here, we studied the cerebellar gene expression patterns of young Sca6-MPI118Q/118Q knockin mice, which recapitulated many phenotypic features of human SCA6. Temporal expression profiles of the candidate genes revealed that the up-regulation of microglial related genes was initiated before PC loss and was augmented as the disease progressed. Histological analysis of the MPI118Q/118Q cerebellum showed the activation of microglia and elevation of Toll-like receptor (TLR) 2, 7 expressions. Genetic ablation of MyD88, TLR-adaptor protein, ameliorated PC loss and partially rescued motor impairments. These results suggest that early neuroinflammatory response may play an important role in the pathogenesis of SCA6.

Free Research Field

神経内科