The Down-Regulation of Clusterin Expression Enhances the ?Synuclein Aggregation Process.

ABSTRACT: Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of ?Synuclein (?Syn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract ?Syn's aggregation, as well as its toxic effects. Clusterin (CLU), a molecular chaperone, was consistently found to interfere with A? 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 ?Syn aggregation process by using SH-SY5Y cells stably overexpressing ?Syn (SH-Syn). First, we showed that ?Syn overexpression caused a strong increase in CLU expression without affecting levels of Hsp27, Hsp70, and Hsp90, which are the chaperones widely recognized to counteract ?Syn burden. Then, we demonstrated that ?Syn 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 ?Syn 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 ?Syn 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 ?Syn burden.

SUBMITTER: Lenzi C 

PROVIDER: S-EPMC7582711 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature