Alpha-Synuclein-Specific T cells in Parkinson's Disease Pathogenesis

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by pathological hallmarks that include dopaminergic neuron death in the substantia nigra, a-synuclein (a-syn) aggregates in Lewy bodies and neurites, neuroinflammation, and immune cell infiltration into the parenchyma. The mechanisms which cause neurodegeneration in PD patients are not fully understood. Moreover, the ways in which immune infiltration into the central nervous system (CNS) affects PD pathogenesis are unclear. Previously published data by our group demonstrates that PD patients have T cells that recognize a-syn, suggesting a role for autoreactive T cells in PD. This data also identified a risk allele, HLA DRB1*15:01, which binds to the a-syn32- 46 peptide with high affinity. Based on these findings, we tested how activation of the adaptive immune response to a-syn in the periphery via immunization with a-syn32-46 in HLA DRB1*15:01 expressing mice may cause PD- like pathology in the CNS. Interestingly, there was no CNS immune or neurodegenerative phenotype, but there was a constipation phenotype and neuron loss in the intestines. This data suggests that activation of the immune response against a-syn alone was insufficient to promote immune infiltration and subsequent PD pathology in the healthy brain. Other mouse models for PD show that a-syn overexpression in the CNS induces infiltration of T cells from the periphery, but it is unclear how infiltrating a-syn-specific T cells contribute to PD pathology. The central hypothesis of this proposal is that activation of the immune response to a-syn in the periphery in combination with a-syn accumulation in the brain promotes immune infiltration, neuroinflammation and neurodegeneration. Aim 1 will assess neuroinflammation and neurodegeneration due to the combinatorial effects of a-syn accumulation in the CNS and peripheral immune activation to the a-syn32-46 peptide using the established immunization model combined with transgenic and viral a-syn overexpression mouse models. Aim 2 will dissect whether a-syn-specific T cells alone are sufficient to induce neuroinflammation and neurodegeneration using adoptive T cell transfer of a-syn-specific T cells from a-syn-immunized mice into unimmunized mice which overexpress a-syn in the CNS. The proposed studies will reveal whether autoreactive a-syn-specific T cells infiltrate the CNS and promote PD pathogenesis. This knowledge may implicate autoimmunity to a-syn as a major driver of PD, and promote the use of immunomodulatory therapies as a PD treatment.