a-Synuclein Promotes Neuronal Dysfunction and Death by Disrupting the Binding of Ankyrin to b-Spectrin

a-Synuclein plays a key role in the pathogenesis of Parkinson's disease and related disorders, but critical interacting partners and molecular mechanisms mediating neurotoxicity are incompletely understood. We show that a-synuclein binds directly to b-spectrin. Using males and females in a Drosophila model of a-synuclein-related disorders, we demonstrate that b-spectrin is critical for a-synuclein neurotoxicity. Further, the ankyrin binding domain of b-spectrin is required for a-synuclein binding and neurotoxicity. A key plasma membrane target of ankyrin, Na+/K+ ATPase, is mislocalized when human a-synuclein is expressed in Drosophila. Accordingly, membrane potential is depolarized in a-synuclein transgenic fly brains. We examine the same pathway in human neurons and find that Parkinson's disease patient-derived neurons with a triplication of the a-synuclein locus show disruption of the spectrin cytoskeleton, mislocalization of ankyrin and Na+/K+ ATPase, and mem-brane potential depolarization. Our findings define a specific molecular mechanism by which elevated levels of a-synuclein in Parkinson's disease and related a-synucleinopathies lead to neuronal dysfunction and death.

Automated summary

This study reveals that a-Synuclein directly binds to b-spectrin, and b-spectrin is critical for a-Synuclein neurotoxicity. The ankyrin binding domain of b-spectrin is required for a-Synuclein binding and neurotoxicity. Mislocalization of Na+/K+ ATPase and membrane potential depolarization are observed when human a-Synuclein is expressed in Drosophila and in Parkinson's disease patient-derived neurons with a triplication of the a-Synuclein locus. These findings define a specific molecular mechanism leading to neuronal dysfunction and death in Parkinson's disease and related a-Synucleinopathies.