Cerebellar ataxias (CAs) encompass a wide spectrum of genetic and sporadic origins, of which a portion is driven by immune-mediated pathomechanisms. While some patients harbor known autoantibodies, assisting diagnosis and treatment, many remain seronegative. Here, we identify synaptophysin (SYP) as an autoantigen in CA by serum IgG staining on primate tissue, combined with human protein array and cell-based assay (CBA). SYP is abundant in presynaptic vesicles and is transiently exposed on the cell surface. Out of 43 patients with CA with synaptic serum reactivity on cerebellar sections, SYP antibodies were identified by CBA in 2 patients. Exposure of human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons to patient's IgG with SYP antibodies causes selective SYP accumulation at the presynaptic membrane. Patient's IgG and SYP monoclonal antibody reduce neuronal populational activity recorded by multi-electrode array. Altogether, we identify SYP as an autoantigen for further stratifying patients with CA. Our functional experiments with SYP antibodies uncover a previously unrecognized mechanism of antibody-mediated synaptic dysfunction.
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