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

ABSTRACT Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. In Parkinson’s disease, the synaptic protein alpha-synuclein (AS) accumulates in neuronal cell bodies and axons. Recent studies indicate that aggregation-prone proteins can spread to other brain cells - such as glia - contributing to progressive deterioration. Although autophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, exact mechanisms are not clear and most work was done in neurons and not on microglial cells. Here we report that AS fibrils but not monomers induce lysosomal damage and autophagy in microglial cells and we extensively characterized the dynamics of this response by both live-cell imaging and correlative light-electron microscopy (CLEM). In addition, we found that autophagy inhibition in these cells impairs mitochondrial quality and leads to microglial cell death. We propose that AS accumulation in lysosomes leads to lysosomal damage, which in turn activates canonical autophagy as a rescue mechanism. Our results provide novel findings about the interaction between AS and the autophagy pathway in microglial cells, which may be important for targeting protein misfolding-associated neurodegenerative diseases.