Feller_2023_Cells_12_

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