2022 Fiscal Year Final Research Report

Analysis of Nna1's genetic changes and explore for optimal treatment methods

Research Project

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Project/Area Number	20K07242
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 48010:Anatomy-related
Research Institution	Niigata University
Principal Investigator	Zhou Li 新潟大学, 研究推進機構, 特任助教 (80568410)
Co-Investigator(Kenkyū-buntansha)	吉岡望新潟大学, 研究推進機構, 助教 (20708375) 竹林浩秀新潟大学, 医歯学系, 教授 (60353439) 中務胞新潟大学, 脳研究所, 助教 (60641579) 崎村建司新潟大学, 脳研究所, フェロー (40162325)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	Nna1 / 顆粒細胞 / 自律的/非自律的な細胞死 / 脊髄
Outline of Final Research Achievements	Nna1 Purkinje cell (PC) or granule cell (GC) cKO mice were generated, respectively. PC Nna1 cKO mice were smaller compared with control ones and began to exhibit ataxia around 20 days after birth. Although most PCs degenerated cell-autonomously by 4 weeks of age, mild motor learning dysfunction was detected in GC Nna1 cKO mice. Apoptotic cells were present in the cerebellar GC layer of both PC and GC Nna1cKO mice, indicating that non-cell-autonomous and cell-autonomous mechanisms coexist in GC death in pcd mice. Furthermore, elevated c-fos expression in the deep cerebellar nucleus and red nucleus of PC Nna1 cKO mice caused motor neuron degeneration in the spinal cord, suggesting that loss of PC leads to excitotoxic motor neuron loss. Hindlimb muscles also expressed atrophy and elevated HSPB5 in PC Nna1cKO mice, providing evidence that PC loss leads to secondary effects such as spinal motor neuron degeneration and muscle stress.
Free Research Field	神経変性疾患
Academic Significance and Societal Importance of the Research Achievements	近年、臨床研究では、人のNna1/CCP1の変異はpcdマウスの神経変性と類似していることが示された（EMBO J, 2018),我々が作成したPCとGCｃKOマウスは細胞自律的と非細胞自律的な観点より細胞死を解明した。プルキンエ細胞が失ったらそれを中心とした神経回路上の橋核と赤核においてはc-fosの発現上昇がみられた（投稿準備中）。グルタミン酸の過剰毒性もしくはGABAの不足と示唆されている。そのために脊髄小脳変性症に治療効果が報告されたGABAアゴニストのバクロフェンを用いて発症前の２週齢と発症後３－４週齢のNna1 nullマウスの脳内に注入し運動失調に与える効果を調べる。