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bioRxiv · 10.1101/2023.01.28.526024

α-synuclein preformed fibrils bind to β-neurexins and impair β-neurexin-mediated presynaptic organization

Feller, B.·Fallon, A.·Luo, W.·Nguyen, P. T.·Shlaifer, I.·Lee, A. K.·Karkout, S.·Bourgault, S.·Durcan, T. M.·Takahashi, H.
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Abstract

Synucleinopathies form a group of neurodegenerative diseases defined by misfolding and aggregation of alpha-synuclein (-syn). Abnormal accumulation and spreading of -syn aggregates lead to synapse dysfunction and neuronal cell death. Yet, little is known about synaptic mechanisms underlying -syn pathology. Here we identified {beta}-isoforms of neurexins ({beta}-NRXs) as presynaptic organizing proteins that interact with -syn preformed fibrils (-syn PFFs), toxic -syn aggregates, but not -syn monomers. Our cell surface protein binding assays and surface plasmon resonance assays reveal that -syn PFFs bind directly to {beta}-NRX through their N-terminal histidine-rich domain (HRD) at nanomolar range (Kd: ~500 nM monomer equivalent). Furthermore, our artificial synapse formation assays show that -syn PFFs diminish excitatory and inhibitory presynaptic organization induced by a specific isoform of neuroligin 1 that binds only {beta}-NRXs, but not -isoforms of neurexins. Thus, our data suggest that -syn PFFs interact with {beta}-NRXs to inhibit {beta}-NRX-mediated presynaptic organization, providing novel molecular insight into how -syn PFFs induce synaptic pathology in synucleinopathies such as Parkinsons disease and dementia with Lewy bodies.

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Feller, B., Fallon, A., Luo, W., Nguyen, P. T., Shlaifer, I., Lee, A. K., Karkout, S., Bourgault, S., Durcan, T. M., Takahashi, H.. 2023-01-30. α-synuclein preformed fibrils bind to β-neurexins and impair β-neurexin-mediated presynaptic organization. https://doi.org/10.1101/2023.01.28.526024

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