Elucidating the Role of LRRK2 in the Central Nervous System: An Examination of Toxin-Induced Neuronal Outcomes

Title: Elucidating the Role of LRRK2 in the Central Nervous System: An Examination of Toxin-Induced Neuronal Outcomes
Authors: Abdel-Messih, Elizabeth
Date: 2016
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Its cause(s) are predominantly unknown; however, a subset of cases has a genetic origin. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of PD. Cases are clinically indistinguishable from idiopathic PD and display incomplete penetrance. Thereby, it is predicted that genetic vulnerability combined with environmental factors cause pathogenesis. However, the identity of these factors is unknown. Unfortunately, LRRK2`s native and pathogenic biological function(s) remain to be defined; owing to obstacles including a complex protein structure and the lack of pathological phenotypes in LRRK2 research models. To address the knowledge gap in LRRK2 biology, we set out to investigate the role of LRRK2 in the central nervous system (CNS). We generated and characterized a disease-mimicking D. melanogaster model of LRRK2-linked PD. This system was utilized to perform an in vivo, unbiased, high-throughput genetic screen to identify candidate interactors of LRRK2. Successful identification of a discrete number of genetic interactors was accomplished and, coupled with published evidence, highlighted the pursuit of subsequent mitochondrial-related investigations of LRRK2. These studies were performed using the M. musculus model system. Since LRRK2 murine models lack disease-relevant phenotypes, and LRRK2’s incomplete penetrance is predicted to be the result of gene-environment interaction, we employed the mitochondrial-targeting exogenous neurotoxin – MPTP/MPP+, to investigate neuronal mitochondrial phenotypes and subsequent survival in the context of LRRK2. Using the pathogenic R1441 GTPase-linked mutation, we did not observe altered neuronal mitochondrial length phenotypes or enhanced CNS sensitization to MPTP/MPP+-induced death; highlighting that MPTP-mediated, mitochondrial-centered mechanisms of action should be approached cautiously in the context of R1441-LRRK2. Collectively, the work presented herein has unveiled novel targets for the exploration of LRRK2 biological function and encourages the investigation of alternative pathogenic trigger mechanisms in the context of LRRK2-linked PD.
URL: http://hdl.handle.net/10393/34751
CollectionThèses, 2011 - // Theses, 2011 -