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2023 Fiscal Year Final Research Report

The pathogenesis of neurodegeneration in the very early stage of polyglutamine disease and the development of nucleic acid therapy in polyglutamine diseases

Research Project

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Project/Area Number 22K15706
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52020:Neurology-related
Research InstitutionNagoya University

Principal Investigator

Hirunagi Tomoki  名古屋大学, 医学部附属病院, 医員 (00927527)

Project Period (FY) 2022-04-01 – 2024-03-31
Keywordsポリグルタミン病 / 球脊髄性筋萎縮症 / 超早期病態 / シナプス関連遺伝子 / 核酸医薬
Outline of Final Research Achievements

This study demonstrated nuclear accumulation of mutant androgen receptor (AR) in motor neurons during the neonatal period in a mouse model of spinal and bulbar muscular atrophy (SBMA). We found that mutant AR induces hyperexcitability in neonatal motor neurons via elevation of synapse-related genes regulated by a transcription repressor, Rest. Further analyses revealed that mutant AR interferes with the repressor activity of Rest by altering its isoforms, resulting in the upregulation of synaptic genes. Furthermore, we showed that intracerebroventricular administration of antisense oligonucleotides that reduce mutant AR or regulate splicing of Rest ameliorates the transcriptional dysregulation, attenuating neuronal excitation and improved the disease phenotype.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、晩発性の疾患であるSBMAにおいても、新生仔期といった超早期に後の神経変性につながる運動ニューロンの過活動が生じていることを明らかとした点、および同時期のASOを用いた治療可能性を示した点で意義がある。また、発達段階における短期間の治療により、成人期以降の神経症状を緩和させるといった本研究で得られたproof of conceptは、SBMAなどのポリグルタミン病だけではなく、他の神経変性疾患にも応用可能であり、これまで根治的な治療法が開発されていない難治性神経疾患に対する、新たな治療戦略につながることが期待される。

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Published: 2025-01-30  

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