α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization.

ABSTRACT: Synucleinopathies form a group of neurodegenerative diseases defined by the misfolding and aggregation of α-synuclein (α-syn). Abnormal accumulation and spreading of α-syn aggregates lead to synapse dysfunction and neuronal cell death. Yet, little is known about the synaptic mechanisms underlying the α-syn pathology. Here we identified β-isoforms of neurexins (β-NRXs) as presynaptic organizing proteins that interact with α-syn preformed fibrils (α-syn PFFs), toxic α-syn aggregates, but not α-syn monomers. Our cell surface protein binding assays and surface plasmon resonance assays reveal that α-syn PFFs bind directly to β-NRXs through their N-terminal histidine-rich domain (HRD) at the nanomolar range (K_D: ~500 nM monomer equivalent). Furthermore, our artificial synapse formatio

SUBMITTER: Feller B 

PROVIDER: S-EPMC10093570 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature