Alpha-synuclein induces autophagy in microglial cells as a consequence of lysosomal damage

BUSSI CLAUDIO; PERALTA RAMOS JAVIER M; ARROYO DANIELA S; GALLEA JOSE I; CELEJ, MARIA S; FLOREY OLIVER; SCHWAB YANNICK; KTISTAKIS NICHOLAS; IRIBARREN PABLO

Carlos Paz

Congreso; Alexander von Humboldt Kolleg. Current Advances on Neurodegeneration: from Molecular Biology to Translational Medicine; 2017

The autophagy pathway plays a crucial role in neurodegenerative diseases, although the precise mechanisms underlying these processes are poorly understood and little is known about the effects of the autophagic process and its regulation on microglial cells.Here we found that exogenous alpha-synuclein fibrils (fAS) but not monomers induced lysosomal damage and autophagy in microglial cells and we studied the dynamics of this response by live-cell imaging. We observed that LC3 is recruited to damaged lysosomes containing fAS and we determined by correlative light-electron microscopy the ultrastructure of these autophagic vesicles.In order to assess the role of autophagy in fAS stimulated microglial cells, we evaluated microglial cell viability by flow cytometry using autophagy inhibitors. We observed mitochondrial quality impairment and microglial cell death after fAS stimulation when autophagy pathway was blocked by FIP200 siRNA or by using the PI3K class III inhibitor spautin-1.In summary, we propose that AS accumulation in lysosomes leads to lysosomal damage, which in turn activates canonical autophagy as a rescue mechanism. Taken together, our results provide new evidence of the autophagic process in fAS-stimulated microglial cells which maybe important for designing novel therapies targeting aggregation-associated degenerative disorders.