Synaptic vesicle proteomics with age and in synucleinopathies

Neurotransmitter release occurs through exocytosis of synaptic vesicles. α-Synuclein’s function and dysfunction in Parkinson’s disease and other synucleinopathies is tightly linked to synaptic vesicle binding. Age is the biggest risk factor for synucleinopathy, and ~15% of synaptic vesicle proteins are linked to diseases of the central nervous system. Yet, age- and disease-induced changes in synaptic vesicles remain unexplored. For an unbiased analysis of the synaptic vesicle proteome, we applied quantitative mass spectrometry to crude synaptic vesicles isolated at three time points (1 month, 3 months, and 10 months of age) from wild-type mice, alpha-synuclein knockout mice, and alpha-synuclein BAC mice, which express human wild-type alpha-synuclein under all human regulatory elements in absence of mouse alpha-synuclein, providing human-like spatiotemporal expression of alpha-synuclein and recapitulating motor and pathological features of Parkinson’s disease. We identified specific changes in synaptic vesicle proteins that capture aging and synucleinopathies. These findings not only provide new insights into synaptic vesicle biology and mechanisms of synucleinopathy, but also offer a baseline for further mechanistic exploration of age- and disease-related alterations in synaptic vesicles.