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Dysregulation of the proteasome increases the toxicity of ALS-linked mutant SOD1.

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/57979

Title: Dysregulation of the proteasome increases the toxicity of ALS-linked mutant SOD1.
Authors: Kitamura, Akira Browse this author →KAKEN DB
Inada, Noriko Browse this author
Kubota, Hiroshi Browse this author →KAKEN DB
Matsumoto, Gen Browse this author →KAKEN DB
Kinjo, Masataka Browse this author →KAKEN DB
Morimoto, Richard I Browse this author
Nagata, Kazuhiro Browse this author →KAKEN DB
Issue Date: Mar-2014
Journal Title: Genes to cells
Volume: 19
Issue: 3
Start Page: 209
End Page: 224
Publisher DOI: 10.1111/gtc.12125
PMID: 24450587
Abstract: A hallmark of protein conformational disease, exemplified by neurodegenerative disorders, is the expression of misfolded and aggregated proteins. The relationship between protein aggregation and cellular toxicity is complex, and various models of experimental pathophysiology have often yielded conflicting or controversial results. In this study, we examined the biophysical properties of amyotrophic lateral sclerosis (ALS)-linked mutations of Cu/Zn superoxide dismutase 1 (SOD1) expressed in human tissue culture cells. Fluorescence correlation spectroscopy (FCS) and Förster resonance energy transfer (FRET) analyses revealed that changes in proteasome activity affected both the expression of FCS- and FRET-detected oligomers and cellular toxicity. Under normal conditions, highly aggregation-prone mutant SOD1 exhibited very little toxicity. However, when the activity of the proteasome was transiently inhibited, only upon recovery did we observe the appearance of ordered soluble oligomers, which were closely correlated with cellular toxicity. These results shed light on the importance of balance in proteostasis and suggest that transient shifts of activity in the cellular machinery can alter the course of protein conformational transitions and dysregulate modulation of proteasome activity. In neurodegenerative disorders including ALS, such changes may be a risk factor for pathogenesis.
Rights: The definitive version is available at wileyonlinelibrary.com
Type: article (author version)
URI: http://hdl.handle.net/2115/57979
Appears in Collections:生命科学院・先端生命科学研究院 (Graduate School of Life Science / Faculty of Advanced Life Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 北村 朗

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