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α-Synuclein Promotes Neuronal Dysfunction and Death by Disrupting the Binding of Ankyrin to β-Spectrin.pdf (4.37 MB)

α-Synuclein Promotes Neuronal Dysfunction and Death by Disrupting the Binding of Ankyrin to β-Spectrin.

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posted on 2024-05-26, 01:45 authored by Gali Maor, Ronald DubreuilRonald Dubreuil, Mel B Feany
α-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 α-synuclein binds directly to β-spectrin. Using males and females in a Drosophila model of α-synuclein-related disorders, we demonstrate that β-spectrin is critical for α-synuclein neurotoxicity. Further, the ankyrin binding domain of β-spectrin is required for α-synuclein binding and neurotoxicity. A key plasma membrane target of ankyrin, Na+/K+ ATPase, is mislocalized when human α-synuclein is expressed in Drosophila Accordingly, membrane potential is depolarized in α-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 α-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 α-synuclein in Parkinson's disease and related α-synucleinopathies lead to neuronal dysfunction and death.SIGNIFICANCE STATEMENT The small synaptic vesicle associate protein α-synuclein plays a critical role in the pathogenesis of Parkinson's disease and related disorders, but the disease-relevant binding partners of α-synuclein and proximate pathways critical for neurotoxicity require further definition. We show that α-synuclein binds directly to β-spectrin, a key cytoskeletal protein required for localization of plasma membrane proteins and maintenance of neuronal viability. Binding of α-synuclein to β-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 α-synuclein neurotoxicity and thus suggest potential new therapeutic approaches in Parkinson's disease and related disorders.

History

Citation

Maor, G., Dubreuil, R. R.Feany, M. B. (2023). α-Synuclein Promotes Neuronal Dysfunction and Death by Disrupting the Binding of Ankyrin to β-Spectrin. Journal of Neuroscience, 43(9), 1614-1626. https://doi.org/10.1523/jneurosci.1922-22.2022

Publisher

Society for Neuroscience

Language

  • en

issn

0270-6474