IRIBARREN PABLO
Congresos y reuniones científicas
Título:
Alpha-synuclein induces autophagy in microglial cells as a consequence of lysosomal damage
Autor/es:
BUSSI, C; PERALTA RAMOS, JAVIER MARÍA; ARROYO DS; GALLEA, JI; CELEJ, MS; FLOREY, OLIVER; SCHWAB, YANNICK; KTISTAKIS, NICHOLAS T.; IRIBARREN, P
Reunión:
Conferencia; Buenos Aires Research Conferences on Autophagy; 2017
Resumen:
Alpha-synuclein induces autophagy in microglial cells as a consequence of lysosomal damageClaudio Bussi1, Javier P. Ramos1, Daniela S. Arroyo1, Jose I. Gallea2, M. Soledad Celej2, Oliver Florey4, Yannick Schwab3, Nicholas Ktistakis4, Pablo Iribarren1*.1Center for Research in Clinical Biochemistry and Immunology (CIBICI-CONICET), Córdoba, Argentina, 2Center for Research in Chemical Biology (CIQUIBIC-CONICET), Córdoba, Argentina, 3EMBL, Cell Biology and Biophysics Unit, Heidelberg, Germany, 4Babraham Institute, Signalling Programme, Cambridge, UK.*corresponding authorThe 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.