Proteomics analysis of autophagy cargos reveals distinct adaptations in PINK1 and LRRK2 models of Parkinson disease

Autophagy is essential for neuronal homeostasis, while defects in autophagy are implicated in Parkinson disease (PD), a prevalent and progressive neurodegenerative disorder. We used unbiased proteomics to compare cargos degraded by basal autophagy in the brain from two mouse models of PD, PINK1-/- and LRRK2G2019S mice. We find evidence for the upregulation of adaptive pathways to support homeostasis in both PD models. In PINK1-/- mice, we observed increased expression of the selective receptor BNIP3 along with evidence of engagement of other alternative pathways for mitophagy. Despite these changes, we find the rate of autophagic flux in PINK1-/- neurons is decreased. In LRRK2G2019S mice, hyperactive kinase activity known to impair autophagosomal and lysosomal function results in increased secretion of extracellular vesicles and autophagy cargo. In support of this observation, we find reduced levels of PIKFYVE, a negative regulator of extracellular vesicle secretion, in both brain and cortical neurons from LRRK2G2019S mice. Thus, distinct adaptive pathways are activated to compensate for perturbations induced by either loss of PINK1 or hyperactivation of LRRK2. Our findings highlight the engagement of compensatory pathways to maintain homeostasis in the brain, and provide insights into the vulnerabilities these compensatory changes may introduce that may further contribute to PD progression. ### Competing Interest Statement J.W.H. is a consultant and founder of Caraway Therapeutics and is a member of the scientific advisory board for Lyterian Therapeutics.