Binding domains of α-synuclein receptors with monomeric/oligomeric α-synuclein: Implications for Parkinson’s disease

Parkinson's disease (PD) and related synucleinopathies are characterized by the pathological aggregation and spread of alpha-synuclein (α-syn), a protein central to neurodegeneration. Currently three neuronal receptors -Family with sequence similarity 171 member A2 (FAM171A2), Lymphocyte Activation Gene 3 (LAG3), and Amyloid-Precursor-Like Protein 1 (APLP1) have been identified as critical mediators of α-syn preformed fibril (PFF) uptake, propagation, and neurotoxicity. Here we utilize AlphaFold 3 program to predict binding domains of respective α-syn receptors with monomer and oliogmer α-syn proteins. Our prediction outcomes show that FAM171A2 protein exhibits a credible interaction interface with α-syn monomer. Whereas AlphaFold3 failed to predict stable complex formation between FAM171A2 and oligomeric α-syn protein. The APLP1 was predicted to interact with both monomeric and hexameric α-syn proteins. However, LAG3 failed to produce a high-confidence binding model with either monomeric or oligomeric α-syn. Neither full-length nor domain-restricted constructs resulted in accurate prediction of the experimentally identified interaction between LAG3 and α-syn protein. Our findings suggest that FAM171A2 may serve as a selective receptor for early-stage α-syn protein transmission. Although there is a lack of no direct interactions between LAG3 and monomeric or oligomeric α-syn, APLP1 may act as an adaptor protein for LAG3 protein to facilitate binding of LAG3 receptor with α-syn proteins. We discuss the pathophysiologic implications of the different binding affinity/domains of α-syn receptors with monomeric/oligomeric α-syn in PD. • FAM171A2, LAG3, and APLP1 are key neuronal receptors mediating α-syn PFF uptake, propagation, and neurotoxicity in PD. • FAM171A2 selectively binds monomeric α-syn via C-term electrostatics, acting as a receptor in early-stage α-syn transmission. • FAM171A2 expression correlates with α-syn burden, serving as a biomarker for early PD detection and progression monitoring. • APLP1 binds mono/oligo α-syn and may act as an adaptor protein facilitating LAG3's interaction with α-syn aggregates. • Targeting the FAM171A2 and APLP1–LAG3 receptor complexes may interrupt α-syn propagation and alleviate PD neurodegeneration.