Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis.

Alpha-synuclein (αSyn) inclusions, termed Lewy bodies, are the characteristic neuropathological feature of Parkinson's disease. Growing evidence points towards a role of aberrant liquid-liquid phase separation in the dysregulation of αSyn and sequence of events that lead to the formation of Lewy bodies. However, the triggers leading to aberrant phase separation are unknown, as is the relevance of this phenomenon to the neurodegeneration process. In this study, we showed that αSyn spontaneously phase separates into condensates in the presence of lipid droplets. These lipid droplet-rich condensates represent a toxic species of αSyn that prevents the turnover of the entrapped lipid droplets; they are also toxic to neighbouring mitochondria which are depolarized and undergo increased mitophagy. These findings underscore the increasing importance of lipid droplets in the pathogenesis of neurodegenerative diseases, and Parkinson's disease in particular. The lipid droplets are significantly enriched within the neuromelanin in midbrain dopaminergic neurons in the substantia nigra and could therefore uniquely facilitate the early αSyn-associated neurodegeneration of this region in PD. Our findings reveal a novel pathway implicated in the dysregulation of αSyn that connects aberrant liquid-liquid phase separation, lipid droplets and mitochondrial toxicity.