Oleg Shupliakov

This grant proposal aims to elucidate the cause and mechanisms of the formation of pathological protein aggregates containing α-synuclein, that lead to neurodegeneration. This group of neurodegenerative diseases, referred to as synucleinopathies, comprises Parkinson's disease, multiple system atrophy, and Lewy body disease. Recent studies have shown that the highest concentration of α-synuclein in neurons occurs in presynaptic nerve terminals within the region of the synaptic vesicle clusters. The liquid phase of synaptic proteins organizes such clusters. Earlier studies have demonstrated that the protein synapsin is essential to maintain the synaptic vesicle liquid phase. Another component of the synaptic vesicle cluster liquid phase is α-synuclein. We suggest that impairment of the regulation of the liquid phase of synaptic vesicles may be the reason for the pathological transition of synuclein from the liquid phase to the solid phase with the formation of protein aggregates. Our preliminary experiments revealed such aggregates in presynaptic terminals. Our main objective is to explain how synuclein-containing aggregates form in nerve terminals and how this process can be stopped or reversed.