Stabilization and Degradation Mechanisms of Cytoplasmic Ataxin-1:

Journal of Experimental Neuroscience

Mayumi F.Kohiyama¹ 

关键词: Ataxin-1;    spinocerebellar ataxia type 1;    14-3-3;    autophagy;    ubiquitin proteasome system;    mTOR;    nuclear inclusions;    aggregation;   

DOI  :  10.4137/JEN.S25469

学科分类：生物科学（综合）

来源: Sage Journals

【 摘 要 】

Aggregation-prone proteins in neurodegenerative disease disrupt cellular protein stabilization and degradation pathways. The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by a coding polyglutamine expansion in the Ataxin-1 gene (ATXN1), which gives rise to the aggregation-prone mutant form of ATXN1 protein. Cerebellar Purkinje neurons, preferentially vulnerable in SCA1, produce ATXN1 protein in both cytoplasmic and nuclear compartments. Cytoplasmic stabilization of ATXN1 by phosphorylation and 14-3-3-mediated mechanisms ultimately drive translocation of the protein to the nucleus where aggregation may occur. However, experimental inhibition of phosphorylation and 14-3-3 binding results in rapid degradation of ATXN1, thus preventing nuclear translocation and cellular toxicity. The exact mechanism of cytoplasmic ATXN1 degradation is currently unknown; further investigation of degradation may provide future therapeutic targets. This review examines the present understanding of cytoplasmic ATXN1 stabilization and potential degradation mechanisms during normal and pathogenic states.

【 授权许可】

CC BY