Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by α-synuclein

a-Synuclein is the major component of Lewy bodies in patients with Parkinson's disease, and mutations in the a-synuclein gene are responsible for some familial forms of the disease. a-Synuclein is enriched in the presynapse, but its synaptic targets are unknown. Synphilin-1 associates in vivo with a-synuclein promoting the formation of intracellular inclusions. Additionally synphilin-1 has been found to be an intrinsic component of Lewy bodies in patients with Parkinson's disease. To understand the role of synphilin-1 in Parkinson's disease, we sought to define its localization and function in the brain. We now report that, like a-synuclein, synphilin-1 was enriched in neurons. In young rats, synphilin-1 was prominent in neuronal cell bodies but gradually migrated to neuropil during development. Immunoelectron microscopy of adult rat cerebral cortex demonstrated that synphilin-1 was highly enriched in presynaptic nerve terminals. Synphilin-1 co-immunoprecipitated with synaptic vesicles, indicating a strong association with these structures. In vitro binding experiments demonstrated that the N terminus of synphilin-1 robustly associated with synaptic vesicles and that this association was resistant to high salt washing but was abolished by inclusion of a-synuclein in the incubation medium. Our data indicated that synphilin-1 is a synaptic partner of a-synuclein, and it may mediate synaptic roles attributed to a-synuclein.