Parkinson disease (PD) is a common neurodegenerative movement disorder characterized pathologically by loss of dopaminergic neurons in the substantia nigra and aggregation of alpha-synuclein (α-syn) into large inclusions. The association of mutations and gene multiplications in SNCA, the gene encoding α-syn, with rare familial forms of PD led to the discovery that α-syn plays a key role in the pathogenesis of PD. The mechanism by which α-syn mediates its toxicity remains uncertain. A leading hypothesis states that the toxic effects of α-syn are mediated by activation of both the innate and adaptive immune systems within the central nervous system. Supporting this hypothesis, post-mortem analysis of PD brains has shown activated microglia surrounding degenerating neurons, T cells infiltrating into brain parenchyma, and the presence of a neurotoxic pro-inflammatory cytokine and chemokine milieu in cerebrospinal fluid. Here, we describe a model whereby aggregated or otherwise post-translationally modified α-syn breaks im-munologic self-tolerance in PD when phagocytosed by activated microglia, induces the production of chemokines that attract lymphocytes, and initiates an autoimmune reaction that ultimately leads to dopaminergic neurotoxicity. Next, we use an α-syn-based mouse model of PD to determine whether the complement system, and particularly complement component 3 (C3), mediates α-syn’s neuroinflammatory and neurodegenerative effects. Finally, we quantify and characterize the phenotypic changes of CD4+ T cells in PD pa-tients compared to caregiver controls, and show an association between disease severity and CD4+ T cell phenotype. Combined, these data demonstrate mechanistic links be-tween α-syn, innate and adaptive immune function, neurodegeneration, and ultimate loss of motor function.
|Advisor:||Standaert, David G.|
|Commitee:||Barnum, Scott R., Benveniste, Etty N., Thannickal, Victor J., West, Andrew B.|
|School:||The University of Alabama at Birmingham|
|School Location:||United States -- Alabama|
|Source:||MAI 55/06M(E), Masters Abstracts International|
|Subjects:||Neurosciences, Medicine, Immunology|
|Keywords:||Adaptive immunity, Alpha synuclein, Complement, Innate immunity, Microglia, Parkinson disease|
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