α-synuclein promotes neuronal dysfunction and death by disrupting the binding of ankyrin to β-spectrin
-synuclein plays a key role in the pathogenesis of Parkinsons disease and related disorders, but critical interacting partners and molecular mechanisms mediating neurotoxicity are incompletely understood. We show that -synuclein binds directly to {beta}-spectrin. Using males and females in a Drosophila model of -synuclein-related disorders we demonstrate that {beta}-spectrin is critical for -synuclein neurotoxicity. Further, the ankyrin binding domain of {beta}-spectrin is required for -synuclein binding and neurotoxicity. A key plasma membrane target of ankyrin, Na+/K+ ATPase, is mislocalized when human -synuclein is expressed in Drosophila. Accordingly, membrane potential is depolarized in -synuclein transgenic fly brains. We examine the same pathway in human neurons and find that Parkinsons disease patient-derived neurons with a triplication of the -synuclein locus show disruption of the spectrin cytoskeleton, mislocalization of ankyrin and Na+/K+ ATPase, and membrane potential depolarization. Our findings define a specific molecular mechanism by which elevated levels of -synuclein in Parkinsons disease and related -synucleinopathies leads to neuronal dysfunction and death. Significance StatementThe small synaptic vesicle associate protein -synuclein plays a critical role in the pathogenesis of Parkinsons disease and related disorders, but the disease-relevant binding partners of -synuclein and proximate pathways critical for neurotoxicity require further definition. We show that -synuclein binds directly to {beta}-spectrin, a key cytoskeletal protein required for localization of plasma membrane proteins and maintenance of neuronal viability. Binding of -synuclein to {beta}-spectrin alters the organization of the spectrin-ankyrin complex, which is critical for localization and function of integral membrane proteins, including Na+/K+ ATPase. These finding outline a previously undescribed mechanism of -synuclein neurotoxicity and thus suggest potential new therapeutic approaches in Parkinsons disease and related disorders.