PINK1, mutated in autosomal recessive Parkinson’s disease, interacts with the proautophagic protein Beclin1 and its antiapoptotic partner Bcl-xL: unraveling the significance of these interactions at the crossroad of multiple neuroprotective pathways

This project represents the continuation of a research line supported by Telethon since 2002, focused on autosomal recessive Parkinson's disease (PD) due to mutations in the PINK1 gene. In particular, the last project aimed at characterizing the interaction between PINK1 and Beclin1, a key pro-autophagic protein. Autophagy is a main cellular mechanism to remove misfolded proteins and aggregates as well as damaged and dysfunctional organelles, and has recently emerged as a critical protective pathway against neurodegeneration. Autophagy suppression results in a marked increase of cell death in vitro and in vivo, and proautophagic drugs are able to reduce protein aggregates and even apoptotic cell death in several models of neurodegenerative diseases. We showed that PINK1 wild type (wt), but not certain mutants, strongly interacts with Beclin1 and positively modulates autophagy under basal and stress conditions. We also found that PINK1 interacts with Bcl-xL, a Beclin1-interacting antiapoptotic protein that plays a crucial protective role within neuronal cells. These results delineate novel exciting pathways through which PINK1 could exert its neuroprotective activity. This renewal project proposes to employ distinct in vitro models of neurodegeneration to characterize the interaction between PINK1 and Beclin1/Bcl-xL, and to investigate its effects on autophagy, apoptosis, mitochondrial dynamics and trafficking. This will provide new insights into the neuroprotective function of PINK1 and the pathogenetic effect on PINK1 mutations. This project holds the great potential to unravel a major protective mechanism against neuronal damage, supporting current research for innovative therapeutic strategies in PD and other neurodegenerative conditions.