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Molecular Pathogenesis of Amyotrophic Lateral Sclerosis Shintaro Tsuboguchi 1 , Tomohiko Ishihara 1,2 , Akihiro Sugai 1 , Akio Yokoseki 3 , Osamu Onodera 1,2 1Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University 2Department of Molecular Neuroscience, Brain Research Institute, Niigata University 3Department of Inter-Organ Communication Research, Niigata University, Graduate School of Medical and Dental Sciences Keyword: TDP-43 , LLPS , 蛋白質分解機構 , RNA代謝 , 自己調節機構 , TDP-43 protein degradation system , RNA metabolism , autoregulation pp.1183-1189
Published Date 2019/11/1
DOI https://doi.org/10.11477/mf.1416201428
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Abstract

The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) has been studied through analysis of the function of the protein produced by the causative genes of familial ALS. The products of these genes are classified as RNA binding proteins, or proteins related to proteolytic systems. However, most case of familial ALS, and sporadic ALS show TAR DNA binding protein-43 (TDP-43) immune-positive cytoplasmic inclusions. Therefore, the molecular mechanism of formation of TDP-43 inclusions and dysfunction caused by TDP-43 inclusions has been studied. As for the mechanism of inclusion formation, non-membrane organelle formation by liquid-liquid phase separation (LLPS) is important. The ubiquitin-proteasome and autophagy systems are important for the degradation of these inclusions. Several genes associated with these systems have been identified as causative genes for ALS. The formation of cytoplasmic inclusions results in the loss of TDP-43 from the nucleus, resulting in abnormalities in RNA metabolism, through the alteration of spliceosomes and Gemini of coiled bodies. Furthermore, in ALS, the regulation of TDP-43 mRNA/protein expression levels has failed. Failure of the autoregulation system facilitates TDP-43 inclusion formation. Development of treatments for ALS based on these elucidated molecular mechanisms is desirable.


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電子版ISSN 1344-8129 印刷版ISSN 1881-6096 医学書院

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