Abstract
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.
Highlights
The cellular proteostasis network (PN) is involved in maintaining proteome integrity with the aim of ensuring cell viability under several stress conditions, including aging, exposure to environmental stress, or disease onset and progression [1]
We found that CLU down-regulation was not accompanied by significant changes of the other chaperones investigated in this study (Figure 9C)
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Summary
The cellular proteostasis network (PN) is involved in maintaining proteome integrity with the aim of ensuring cell viability under several stress conditions, including aging, exposure to environmental stress, or disease onset and progression [1]. Only the expression of CLU was increased in all the intracellular fractions and in the culture conditions (data not shown), albeit with different protein patterns among the fractions analyzed (Figure 5A,B). ΑSyn was detected in the extracellular environment but without a significant difference between SH-SynsiRNA-T and SH-SynNC-T (Figure 9B) Under these conditions, we found that CLU down-regulation was not accompanied by significant changes of the other chaperones investigated in this study (Figure 9C).
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