Rose, J.; (2010) Molecular chaperone modulation of Parkin aggregation and function in a cell model of Parkinson’s disease. Doctoral thesis , UCL (University College London).

Abstract

Mutations in the E3 ubiquitin ligase Parkin are associated with autosomal recessive juvenile Parkinsonism. Furthermore, Parkin is recruited to Lewy bodies in brains of patients with sporadic Parkinson’s disease (PD), suggesting a role for Parkin in the pathogenesis of PD. This study investigated the effect of the DnaJ/Hsp40-like protein HSJ1 (DnaJB2) on Parkin biology. HSJ1 proteins are neuronal cochaperones that regulate Hsp70 activity through their J domain and exploit ubiquitin interaction motifs (UIM) to promote sorting of misfolded ubiquitylated proteins to the proteasome for degradation. Disease-related mutant forms of Parkin formed inclusions when overexpressed in neuronal cells. Co-expression of mutant Parkin with HSJ1a significantly reduced inclusion formation and altered inclusion characteristics. The effect of HSJ1a on Parkin inclusions required a functional J domain. Mutant Parkin could be co-immunoprecipitated with HSJ1a. Wild-type Parkin was also co-immunoprecipitated with HSJ1a, suggesting a potential interaction with normal Parkin. Importantly, HSJ1a enhanced the E3 ubiquitin ligase activity of wild-type Parkin, dependent on the HSJ1 UIM domain. HSJ1 and Parkin promoted the degradation of the Parkin substrate Synphilin-1. Finally, it was confirmed that Parkin relocates to mitochondria upon mitochondrial membrane depolarization. Moreover, Parkin induced the selective elimination of impaired mitochondria by mitophagy. Interestingly, HSJ1 rescued the relocation of Parkin mutants to damaged mitochondria and partially restored mutant Parkin’s ability to induce mitophagy. These data show that HSJ1 proteins may affect Parkin aggregation and function, which may have a broader relevance to PD.

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