Neuronal surface-directed antibodies (NSAbs) have pathogenic potential. This project aims to determine the presence and target(s) of NSAbs in patients with idiopathic Parkinson's disease (PD). We aim to ask if autoantibodies to novel or established targets are present at onset of PD, or whether they develop during the disease course. These antibodies may be pathogenic but, more likely, could modify disease course and prognosis and justify immunotherapies.
We will examine binding to cultured live hippocampal and dopaminergic neurons using 64 available paired sera and CSFs from PD patients at diagnosis, 198 patients with endophenotypes of PD, and IgG extracted from PD-patient brains. Also, to study patient-specific neuronal antigen expression, we will determine binding of patient IgG to their own inducible-pluripotent stem cell-derived dopaminergic neurons. The presence of NSAbs in any of theses systems will initiate proteomic methods to detect novel antigens. In addition, autoantibody binding to a prominent candidate antigen in PD, alpha-synuclein, will be tested using cell-based assays currently under development.
This study aims to use complementary approaches to determine the presence of disease-relevant autoantibodies in PD. This has relevance for mechanisms of disease initiation and perpetuation with the potential for biomarker development or even disease-modification with immunotherapies.