Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson's Disease

Multiple-system trophy (MSA) and Parkinson's Disease (PD) are both progressive, neurodegenerative diseases characterized by neuropathological deposition of aggregated alpha-synuclein (alpha Syn). The causes behind this aggregation are still unknown. We have reported aberrancies in MSA and PD patients in naturally occurring autoantibodies (nAbs) against alpha Syn (anti-alpha Syn-nAbs), which are important partakers in anti-aggregatory processes, immune-mediated clearance, and anti-inflammatory functions. To elaborate further on the timeline of autoimmune aberrancies towards alpha Syn, we investigated here the Immunoglobulin (Ig) affinity profile and subclass composition (IgG-total, IgG1-4 and IgM) of anti-alpha Syn-nAbs in serum samples from prodromal (p) phases of MSA and PD. Using an electrochemiluminescence competition immunoassay, we confirmed that the repertoire of high-affinity anti-alpha Syn-nAbs is significantly reduced in pMSA and pPD. Further, we demonstrated that pPD had increased anti-alpha Syn IgG-total levels compared to pMSA and controls, concordant with increased anti-alpha Syn IgG1 levels in pPD. Anti-alpha Syn IgG2 and IgG4 levels were reduced in pMSA and pPD compared with controls, whereas anti-alpha Syn IgG3 levels were reduced in pMSA compared to pPD and controls. The results indicate that the impaired reactivity towards alpha Syn occurs prior to disease onset. The apparent lack of high-affinity anti-alpha Syn nAbs may result in reduced clearance of alpha Syn, leading to aggregation of the protein. Thus, this study provides novel insights into possible causes behind the pathogenesis in synucleinopathies such as MSA and PD.