Novel Naturally Occurring Autoantibodies Attenuate Α‐synuclein Pathology in a Mouse Model of Parkinson's Disease

AIMS:Accumulation and propagation of pathological α-synuclein (α-Syn) are the major contributing factors to the pathogenesis of Parkinson's disease (PD). Therapy to halt the spreading of α-Syn pathology needs to be established.METHODS:After phage display and affinity maturation, human-derived anti-α-Syn autoantibodies were selected and applied to biochemical, cellular and animal models of PD.RESULTS:The novel naturally occurring anti-α-Syn autoantibodies (α-Syn-nAbs), P21 and P22, selectively bind α-Syn preformed fibrils (PFFs), recognise Lewy bodies (LBs) and Lewy neurites (LNs) in human PD brains, block α-Syn fibrillization and inhibit the seeding of α-Syn PFFs. Moreover, systematic administration of P21 and P22 attenuates α-Syn pathology, degeneration of the nigrostriatal pathway and motor deficits in mice injected with α-Syn PFFs.CONCLUSIONS:P21 and P22 attenuate α-synuclein pathology and are promising candidates for PD treatment.