Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells

BUSSI, CLAUDIO; PERALTA RAMOS, JAVIER M.; ARROYO, DANIELA S.; GALLEA, JOSE I.; RONCHI, PAOLO; KOLOVOU, ANDRONIKI; WANG, JI M.; FLOREY, OLIVER; CELEJ, MARIA S.; SCHWAB, YANNICK; KTISTAKIS, NICHOLAS T.; IRIBARREN, PABLO

JOURNAL OF CELL SCIENCE

COMPANY OF BIOLOGISTS LTD

Año: 2018 vol. 131

0021-9533

utophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, but the exact mechanisms and causal connections are not clear and most previous work was done in neurons and not in microglial cells. Here, we report that exogenous fibrillary, but not monomeric, alpha-synuclein (AS, also known as SNCA) induces autophagy in microglial cells. We extensively studied the dynamics of this response using both live-cell imaging and correlative light-electron microscopy (CLEM), and found that it correlates with lysosomal damage and is characterised by the recruitment of the selective autophagy-associated proteins TANK-binding kinase 1 (TBK1) and optineurin (OPTN) to ubiquitylated lysosomes. In addition, we observed that LC3 (MAP1LC3B) recruitment to damaged lysosomes was dependent on TBK1 activity. In these fibrillar AS-treated cells, autophagy inhibition impairs mitochondrial function and leads to microglial cell death. Our results suggest that microglial