All ETDs from UAB

Advisory Committee Chair

Andrew D West

Advisory Committee Members

Malu G Tansey

Etty Benveniste

Chander Raman

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Parkinson disease (PD) is a late onset, progressive neurodegenerative movement disorder with cardinal symptoms of tremor at rest, bradykinesia, postural instability, and rigidity. These motor symptoms of PD are caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, despite PDs first modern observation in 1817, little is understood about the causes and molecular mechanisms behind dopaminergic neuron loss. The relatively weak understanding of pathological mechanisms has hindered the development of treatments to slow or halt the progression of PD. However, recently, mounting evidence from post-mortem, imaging, and retrospective studies suggest an important role for inflammation in the etiology of PD. Post-mortem analysis has implicated an elevated level of pro-inflammatory cells and cytokines in the brains and cerebrospinal fluid of patients with PD compared to control. Dopaminergic cells in the SNpc have been suggested to be particularly sensitive to these cells and cytokines found in post-mortem analysis, making the examination of inflammation as a pathological modifier or cause of PD of high therapeutic interest. Familial studies of PD have yielded some clues to target inflammation in the study of PD. From these studies, mutations in leucine rich repeat kinase 2 (LRRK2) have been shown to be the largest genetic cause of PD. Outside of PD, LRRK2 is genetically and biochemically linked to inflammation. Genetically, LRRK2 is associated with inflammatory disorders such as leprosy and Crohn's Disease through genome wide association studies. At a biochemical level, expression studies show very high LRRK2 protein abundance in innate immune cells. Genetic or pharmacological manipulation of LRRK2 results in altered immune response, making LRRK2 an excellent mechanism to study inflammation in PD. Throughout this dissertation, we will utilize genetic manipulations of LRRK2 to knockout or overexpress kinase active forms of LRRK2 coupled with robust models of inflammation both in vitro and in vivo to understand how LRRK2 influences immune cells and provide insight into inflammatory mechanisms in PD.

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