Theses Doctoral

The role of a-Synuclein-specific T cells in Parkinson’s disease

Monahan, Connor

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. The main symptoms of PD include tremor, muscle stiffness, slowness of movement, and postural instability. Motor symptoms of PD are driven by pathology primarily in the substantia nigra (SN) region of the brain, where there is dopaminergic neuron death and a-Synuclein (a-Syn) protein aggregation. Simultaneously, there is persistent inflammation in the central nervous system (CNS) and in the periphery of PD patients that begins prior to the onset of motor symptoms. Animal models of PD can exhibit inflammation in the brain and periphery, but the role of the immune system in disease pathogenesis and progression is not fully understood.

In Chapter 1, I introduce PD neuropathology, genetic and environmental risk factors, and hypotheses for a-Syn aggregation and propagation from the periphery to the brain. Then, I discuss the altered immune responses and features of autoimmunity in PD patients. Lastly, I describe animal models of PD and how they are used to investigate the role of the immune system in PD pathology.

Features of autoimmunity against the a-Syn protein are present in PD patients and appear prior to the onset of motor symptoms. Whether autoimmunity to a-Syn can alone initiate PD pathology has not been tested in animal models of PD. In Chapter 3, I demonstrate that activation of a-Syn32-46-specific CD4+ T cells in transgenic humanized mice induced early features of PD in the gut. We found that humanized mice immunized with a-Syn32-46 experience constipation, a common early PD symptom, as well as enteric neuron loss. Further investigation into the immune response in the gut revealed activated innate and adaptive immune responses which promoted dopaminergic neuron loss in the small intestines. PD pathology, however, did not develop in the brain, suggesting that autoimmunity to a-Syn32-46 promotes pathology at prodromal PD stages.

Elevated T cell infiltration is found in the PD patient brain, suggesting that the adaptive immune response may also promote pathology in the brain at later disease stages. I hypothesized that a-Syn-specific CD4+ T cells may promote PD neuropathology upon a-Syn aggregation. In Chapter 4, I tested this hypothesis in both humanized and wild-type mice. I found that active immunization with a-Syn32-46 in humanized mice combined with human a-Syn overexpression in the brain did not increase T cell CNS infiltration. However, adoptive transfer of a-Syn-specific T cells into wildtype mice that overexpress human a-Syn increases T cell CNS infiltration and CNS myeloid cell activation. These results suggest that a-Syn-specific T cells may promote neuroinflammation in the presence of a-Syn accumulation.

In Chapter 5, I summarize the major findings from my research and future directions which can provide a more detailed understanding of the ways that a-Syn-specific T cells promote PD neuropathology. Furthermore, I discuss innovations in the diagnosis and treatment of PD and the potential for immunotherapies to significantly modify disease course.

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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Sulzer, David L.
Degree
Ph.D., Columbia University
Published Here
January 15, 2025