The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process

International Journal of Molecular Sciences

Saverio Bettuzzi¹  Federica Rizzi¹  Chiara Lenzi¹  Ileana Ramazzina¹  Isabella Russo²  Alice Filippini² 

[1] Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy;Department of Molecular and Translational Medicine, University of Brescia, Via Europa 11, 25123 Brescia, Italy;

关键词: clusterin;    αSynuclein;    proteostasis;    chaperone;    protein aggregation;    heat shock protein;   

DOI  :  10.3390/ijms21197181

来源: DOAJ

【 摘 要 】

Parkinson’s Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of αSynuclein (αSyn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract αSyn’s aggregation, as well as its toxic effects. Clusterin (CLU), a molecular chaperone, was consistently found to interfere with Aβ aggregation in Alzheimer’s Disease (AD). However, its role in PD pathogenesis has yet to be extensively investigated. In this study, we assessed the involvement of CLU in the αSyn aggregation process by using SH-SY5Y cells stably overexpressing αSyn (SH-Syn). First, we showed that αSyn overexpression caused a strong increase in CLU expression without affecting levels of Hsp27, Hsp70, and Hsp90, which are the chaperones widely recognized to counteract αSyn burden. Then, we demonstrated that αSyn aggregation, induced by proteasome inhibition, determines a strong increase of CLU in insoluble aggregates. Remarkably, we revealed that CLU down-regulation results in an increase of αSyn aggregates in SH-Syn without significantly affecting cell viability and the Unfolded Protein Response (UPR). Furthermore, we demonstrated the direct molecular interaction between CLU and αSyn via a co-immunoprecipitation (co-IP) assay. All together, these findings provide incontrovertible evidence that CLU is an important player in the response orchestrated by the cell to cope with αSyn burden.

【 授权许可】

Unknown