All ETDs from UAB

Advisory Committee Chair

David G Standaert

Advisory Committee Members

Laurie E Harrington

Hui Hu

Matthew S Goldberg

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Synucleinopathies, which include Parkinson disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are a collection of neurodegenerative diseases that are in major part defined by the presence of alpha-synuclein (α-syn) rich protein aggregates in the brain. Increasing evidence has highlighted a neuroinflammatory phenotype also associated with these synucleinopathies. This neuroinflammatory phenotype includes the activation of central nervous system (CNS) microglia, increased pro-inflammatory cytokines, and the infiltration of peripheral T cells into the CNS. We sought to further explore the T cell responses associated with PD and MSA. Using two preclinical mouse models of PD and MSA, our studies have provided evidence that in response to α-syn overexpression in the CNS, T cells do indeed infiltrate into the parenchyma. These parenchymal T cells are predominantly CD4 T “helper” (Th) cells that produce the pro-inflammatory cytokine IFN-γ. Subsequently, we determined that the genetic knockout or pharmacological depletion of T cells could reduce the neuroinflammation and CNS damage associated with α-syn pathology. More specifically, knockout of CD4 T cells, but not CD8 T cells, was able to reduce the activation status of CNS myeloid cells in both PD and MSA models. Similarly, knockout of CD4 T cells, but not CD8 T cells, was associated with myelin protection in the MSA model and dopamine neuron protection in the PD model—key CNS populations affected in human synucleinopathies. Additionally, for the first time, we observed robust infiltration of CD4 and CD8 T cells in the CNS postmortem tissue of MSA patients. Collectively, these results indicate that T cells make up a part of the neuropathology of PD and MSA. Their overall contribution to the diseases remains unclear but ours and other’s evidence would suggest that they may be promoting an overall neuroinflammatory as well as neurodegenerative response to α-syn pathology. Broadly, these findings could provide potential therapeutic targets to dampen the immune response associated with synucleinopathies in hopes of modifying the disease course.

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