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

Lugar: Cambridge; Año: 2018

0021-9533

utophagic dysfunction and protein aggregation have been linked to severalneurodegenerative disorders, but the exact mechanisms and causal connections are notclear and most work was done in neurons and not in microglial cells. Here we report thatexogenous fibrillar but not monomeric alpha-synuclein (AS) induces autophagy inmicroglial cells. We extensively studied the dynamics of this response by both live-cellimaging and correlative light-electron microscopy (CLEM) and found that it correlates withlysosomal damage and is characterised by the recruitment of the selective autophagyassociatedproteins TANK-binding kinase 1 (TBK1) and Optineurin (OPTN) toubiquitinated lysosomes. In addition, we observed that LC3 recruitment to damagedlysosomes was dependent on TBK1 activity. In these fibrillar AS-treated cells, autophagyinhibition impairs mitochondrial function and leads to microglial cell death. Our resultssuggest that microglial autophagy is induced in response to lysosomal damage caused