Abstract - Korobeinikov

Alpha-synuclein is an essential protein for the synaptic vesicles cycle, highly enriched in neuronal synapses. However, in disease, it often relocates to the soma, forming the aberrant inclusions—Lewy bodies (LBs), which disrupt neuronal function and lead to cognitive and motor deficits. Despite being the hallmark of synucleinopathies, the formation mechanism of LBs remains unclear. To decipher the initial stages of LB genesis, we employed the minimal reconstitution system of alpha-synuclein and its interaction partner— synphilin 1. Utilizing live-cell confocal microscopy and soft Xray tomography in cellular systems, we were able to recapitulate the formation of LB-like inclusions. We then employed C. elegans as a model to ectopically generate these aberrant inclusions in body wall muscle cells. LB-like structures demonstrated the characteristic core-shell arrangement and recapitulated the accumulation of membrane-bound organelles such as mitochondria, another hallmark of disease. Together, our current data suggest that LB-like structures may arise from the aberrant liquid-liquid phase separation of alpha-synuclein and its interactor proteins, leading to the formation of insoluble inclusions and disruption of intracellular organelles.