Distinct adaptations revealed by unbiased proteomic analysis of autophagy cargos in the brain in PINK1 and LRRK2 models of Parkinson’s disease

Abstract

ABSTRACTAutophagy is a conserved and essential cellular degradation and recycling process that is required to maintain neuronal homeostasis. Genetic and pathological evidence suggest that autophagy is disrupted in Parkinson’s disease (PD), a prevalent and progressive neurodegenerative disease, yet how changes in autophagy contribute to disease pathogenesis is unclear. To better understand the cellular impacts of disrupted autophagy on neuronal function, we used unbiased proteomics to compare the cargos degraded by basal autophagy in two different mouse models of PD. We isolated autophagic vesicles from the brains of PINK1 knock-out mice and LRRK2G2019Sknock-in mice, and further compared these data to observations from young and old mice. We find evidence for the upregulation of adaptive pathways to remove proteins and organelles in PINK1-/-and LRRK2G2019Smice. In PINK1-/-mouse brain, impaired mitophagy leads to increased expression of components of the autophagic machinery as well as increased expression of selective adaptors for mitochondrial autophagy independent of PINK1/Parkin, including BCL2L13. In LRRK2G2019Smice, we find that the impairments to autophagosome trafficking and acidification lead to increased cargo secretion. We further compared these data sets to proteomic data comparing young and old mice. In aged mice, we find decreased engulfment of lysosomes and increased engulfment of α-synuclein, a key component of pathogenic Lewy bodies found in PD. Together, these findings highlight the engagement of distinct compensatory pathways to maintain homeostasis in the brain upon disruption of either stress-induced or basal autophagic pathways, and we begin to identify how age-related changes may place further stress on autophagy’s ability to maintain homeostasis.Graphical Abstract