elucidation of pathomechanism in sporadic ALS

2014 Fiscal Year Final Research Report

• Project/Area Number: 22590965
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: SASAKI SHOICHI 東京女子医科大学, 医学部, 准教授 (40119962)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 筋萎縮性側索硬化症 / オートファジー / TDP-43 ノックアウトマウス / AMPA 受容体 / RNA 編集 / ADAR2-ノックアウトマウス / カルシウム / 血液-脊髄関門

Outline of Final Research Achievements

(1) In amyotrophic lateral sclerosis (ALS), TDP-43 trafficking between the nucleus and the cytoplasm is disturbed, resulting in an accumulation of TDP-43 in the cytoplasm in the form of insoluble aggregates. (2) Autophagy is significantly activated in the cytoplasm of motor neurons in sporadic ALS and may be involved in the pathomechanism of the neurodegeneration of motor neurons. (3) ADAR2-reduction is associated with progressive deterioration of nuclear architecture, resulting in vacuolated nuclei due to a Ca2+-permeable AMPA receptor-mediated mechanism. (4) Significantly increased autophagy flux in the degenerating motor neurons of ADAR2-knockout mice likely resulted from Ca2+ overload. (5) The temporary and reversible breakdown of the blood-spinal cord barrier at the early symptomatic stage could be a direct pathogenic consequence of the loss of TDP-43 protein in TDP conditional knockout mice.

Free Research Field

神経内科学