Therapy development for neuromuscular degeneration in motor neuron diseases

2016 Fiscal Year Final Research Report

• Project/Area Number: 26293206
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: KATSUNO Masahisa 名古屋大学, 医学(系)研究科(研究院), 教授 (50402566)
• Co-Investigator(Kenkyū-buntansha): 祖父江 元 名古屋大学, 医学(系)研究科(研究院), 特任教授 (20148315) ; 近藤 直英 名古屋大学, 医学部附属病院, 医員 (20725527) ; 佐橋 健太郎 名古屋大学, 医学部附属病院, 医員 (90710103)
• Co-Investigator(Renkei-kenkyūsha): OKADA Yohei 愛知医科大学, 医学部, 特任准教授 (30383714)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 運動ニューロン / 骨格筋 / エピジェネティクス / ミトコンドリア / NFkB

Outline of Final Research Achievements

We exploited antisense oligonucleotides (ASOs) to inhibit mutant androgen receptor (AR) RNA levels in the central nervous system and explored its therapeutic effects in the model mouse of spinal and bulbar muscular atrophy (SBMA) that harbors mutant AR gene with 97 CAGs. Intracerebroventricular ASO administration in the SBMA mice efficiently suppressed the mutant gene expression in the central nervous system, highlighting the neurotoxicity of mutant AR in motor neurons. RG108, an inhibitor of DNA methylation suppressed motor neuron degeneration in the SBMA mouse, suggesting that the mutant AR-induced hypermethylation of DNA is implicated in the pathomechanism of SBMA. Both motor neurons and skeletal muscles of the SBMA mouse showed mitochondrial dysfunction, up-regulation of oxidative stress, and activation of NFkB signaling, all of which were mitigated by a PPARgamma agonist pioglitazone, suggesting common molecular pathways in the neuro-muscular degeneration in SBMA.

Free Research Field

神経内科学