α-synuclein cooperates with CSPα in preventing neurodegeneration

alpha-synuclein and cysteine-string protein-a (CSP alpha) are abundant synaptic vesicle proteins independently linked to neurodegeneration. Dominantly inherited mutations in alpha-synuclein cause Parkinson's disease, but the physiological role of alpha-synuclein remains unknown. Deletion of CSP alpha produces rapidly progressive neurodegeneration in mice, presumably because the cochaperone function of CSP alpha is essential for neuronal survival. Here, we report the surprising finding that transgenic expression of a-synuclein abolishes the lethality and neurodegeneration caused by deletion of CSP alpha. Conversely, ablation of endogenous synucleins exacerbates these phenotypes. Deletion of CSP alpha inhibits SNARE complex assembly; transgenic alpha-synuclein ameliorates this inhibition. In preventing neurodegeneration in CSP alpha-deficient mice, alpha-synuclein does not simply substitute for CSP alpha but acts by a downstream mechanism that requires phospholipid binding by alpha-synuclein. These observations reveal a powerful in vivo activity of alpha-synuclein in protecting nerve terminals against injury and suggest that this activity operates in conjunction with CSP alpha and SNARE proteins on the presynaptic membrane interface.