Examining Parkinson’s Disease Linked DJ-1 and its Interaction with Autophagy Related ATG5 and ATG12 & Understanding PINK1’s Functional Interaction with Mitochondrial m-AAA Protease AFG3L2

Abstract

Mutations in DJ-1 and PTEN-induced putative kinase 1 (PINK1) have been linked to familial early-onset Parkinson’s disease. However, their functional role is not well understood. Through a mass-spectrometry screen we identified protein interaction candidates ATG5 and ATG12 for DJ-1 and AFG3-like AAA ATPase 2 (AFG3L2) for PINK1. Examination of ATG5, ATG12, and DJ-1 by co-immunoprecipitation through multiple methods, did not validate the interaction. In contrast, the interaction between m-AAA protease AFG3L2 and PINK1 was validated. AFG3L2 selectively stabilized and can differentially cleave PINK1 in-vitro. We observed endogenous mitophagy in AFG3L2 null cells. Furthermore, we elucidated a novel function of mitochondrially-targeted PINK1 fragments in rescuing endogenous mitochondrial fragmentation, increasing both mitochondrial length and networking. Although further examination is needed, these studies provide a greater understanding of the functional interaction between PINK1 and AFG3L2 and provide evidence that DJ-1, ATG5 and ATG12 may not interact.