All ETDs from UAB

Advisory Committee Chair

David G Standaert

Advisory Committee Members

Etty N Benveniste

Daniel C Bullard

Louis B Nabors

Erik D Roberson

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Parkinson disease (PD) is the most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator of PD with many of the inflammatory manifestations of human PD cases recapitulated in animal models of PD. We began by examining the inflammatory potential of α-syn fibrils, a newly characterized α-syn conformation that is neurotoxic and prion-like in its endogenous α-syn recruitment and cellular transmission. Our studies provide evidence that the α-syn fibrils evoke a pro-inflammatory response in murine primary microglia, resulting in an increase in expression in a milieu of pro-inflammatory cytokines and chemokines, increases in inducible nitric oxide synthase (iNOS), and increased antigen processing and presentation. Subsequently, we studied factors involved in microglial activation and preserving microglial quiescence: microRNAs, small regulatory units in the cell that moderate and translationally repress messenger RNA; and fractalkine signaling, a neuron to microglia signaling pathway involved with maintaining microglial quiescence. In a mouse model that virally overexpresses human α-syn, we identified microRNA-155 (miR-155), a strong pro-inflammatory microRNA, to be upregulated in response to α-syn. Genetically knocking out miR-155 resulted in ablated α-syn induced neuroinflammation and proved neuroprotective. Primary microglia with miR-155 knocked out recapitulated the in vivo lack of neuroinflammation when exposed to α-syn but the inflammation was restored when a synthetic mimic of miR-155 was added. Blockade of fractalkine signaling by genetic deletion of the signaling receptor, CX3CR1, in the same model proved to reduce neuroinflammation and neurodegeneration. This result is different from that previously described in neurotoxin models of PD, suggesting important differences in the underlying biology. Collectively, these results indicate that abnormal forms of α-syn, specifically fibrils, generate a pro-inflammatory response similar to what is seen in human PD. Targeting microglia, either by microRNA modulation or fractalkine signaling, reduces the inflammatory response and can even be neuroprotective. These findings provide important mechanistic insights into PD and provide potential novel treatment strategies.

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