Increasing evidence suggests that neurotoxic inflammatory activities affect pathogenesis and progression of Parkinson's disease (PD). Neuroinflammatory processes also produce oxidized and modified self-CNS proteins which lead to dysfunction, misfolding, aggregation, and retention of those oxidized products. In PD, nitrated a-synuclein (N-a-syn) is found aggregated within the cytoplasm and Lewy bodies of dopaminergic neurons within the substantia nigra and is released to the extraneuronal environment by dying and damaged neurons. We demonstrated that after 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) intoxication, N-a-syn is readily detected in ventral midbrain and cervical lymph nodes (CLN), but not other secondary lymphoid tissues;activates microglia and antigen presenting cells (APCs);and is recognized by the adaptive immune system whereas unmodified a-synuclein is not recognized. Moreover, N-a-syn-specific T cells exacerbate MPTP-induced microglia-mediated inflammation and subsequent neurodegeneration. We hypothesize that the tempo and progression of PD is accelerated by N-a-syn stimulation of microglia and APCs, recognition by the adaptive immune system of neoantigenic epitopes on N-a-syn, and induction of effector T cells that extravasate to neuroinflammatory sites, exacerbate inflammatory microglia, and augment microglia-mediated neurotoxicity. Thus this proposal seeks to elucidate the induction and role of T cell-mediated immunity in the pathogenesis of Parkinson's disease. To test our hypothesis, 3 proposed aims will determine 1) the N-a-syn epitopes and MHC elements permissive for induction of T helper cells that mediate dopaminergic neurodegeneration, 2) N-a-syn-specific T helper effector subset(s) responsible for exacerbated neurodegeneration, and 3) molecular and biochemical mechanisms by which N-a-syn specific Teff subset(s) modulate neurodegeneration.
While Parkinson's disease (PD) is linked to neuroinflammation and neurodegeneration due to proinflammatory cytokines, chemokines, reactive intermediates, and neurotoxins, we have shown in an experimental model of PD that nitrated a-synuclein, a component commonly found in dopaminergic neurons and Lewy body inclusions in PD patients, elicits both innate and T cell responses which exacerbate inflammation and neurodegeneration. We propose to delineate which antigens and cellular components permit the induction of these antigen- specific effector T cells and which effector T cells are responsible for augmenting neuroinflammation and neurodegeneration. Using state of the art proteomic and genomic techniques and functional blockade assays, we propose to delineate the biochemical and molecular factors by which effector T cells exacerbate inflammation and neurodegeneration, and validate their relevance in two complementary models of PD neurodegeneration.
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