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