Coronin1A regulates the trafficking of alpha synuclein in microglia.

Microglia respond to cytotoxic protein aggregates associated with the progression of neurodegenerative disease. Pathological protein aggregates activate the microglial NLRP3 inflammasome resulting in proinflammatory signaling, secretion, and potentially pyroptotic cell death. We characterized mixed sex primary mouse microglia exposed to microbial stressors and alpha synuclein preformed fibrils (αsyn PFFs) to identify cellular mechanisms related to Parkinson's disease. Microglia package and release the endosome fate regulator Coronin1A (Coro1A) in EVs in an -dependent manner in widely used experimental activation conditions. We were surprised to find that Coro1A packaging and release was not -dependent in αsyn PFF exposure conditions. microglia exposed to αsyn PFFs trafficked more αsyn to lysosomal compartment increasing lysosomal membrane permeabilization. This corresponds to a decrease in αsyn released in EVs suggesting that Coro1A functions to shunt pathological proteins to a secretory pathway to attenuate lysosomal stress. αsyn PFF driven lysosomal stress resulting from loss was associated with enhanced cytotoxicity. Intrinsic apoptosis signaling was unaffected, but we observed elevated cytosolic cathepsin B and the presence of a cathepsin associated 55kD PARP cleavage product. Post-mortem analysis of the PD mesencephalon supported a role for Coro1a in microglia, revealing elevated levels of Coro1A protein in human PD brains compared to those of healthy donors. Findings are relevant to the distribution of pathological αsyn and indicate that protects microglia from lysosomal overload, inflammasome activation, and pyroptotic demise. Microglia are responsible for clearing toxic protein aggregates such as alpha synuclein (αsyn) in Parkinson's Disease (PD). PD is slowly progressive, implying that microglia are under proteinaceous stress for an extended time, maintaining some level of homeostasis while attempting to clear pathologically aggregated proteins. Pathological proteins can overload the lysosomes resulting in rupture, decreasing the ability of microglia to clear protein aggregates, and contributing to a hyperreactive inflammatory state. We determined that the protein Coronin1A functions in microglia to attenuate αsyn-induced lysosomal stress, preventing Nlrp3-inflammasome activation, and cell death. These findings identify a protective cellular mechanism operating in microglia that may contribute to the distribution of pathological proteins into the microenvironment.