Parkinson’s disease (PD) is a common neurodegenerative disorder symptomatically characterized by motor dysfunction caused by the selective loss of nigral dopamine neurons within midbrain. The pathogenesis of PD remains unclear. Although, originally thought to be sporadic, about ten percent of PD is familial. The recent elucidation of mutations in genes linked to the disease has offered potential for new animal models and understanding of PD pathogenesis. DJ-1 and LRRK2 are genes linked to autosomal recessive juvenile-onset PD and autosomal-dominant late onset PD, respectively. How mutations in these two genes leads to PD remains uncertain and is plagued by poor murine models that do not recapitulate the human condition. The following dissertation attempts to characterize both mouse and fly models of DJ-1 and LRRK2 mediated PD and elucidate other genetic modifiers that may contribute to PD. Firstly, the DJ-1 null mouse model, which lacks cell death, was improved by backcrossing to a pure C57-Bl6 background. These DJ-1 null mice display a robust and progressive unilateral-to-bilateral loss of nigral neurons accompanied by motor deficits in aged mice. Secondly, a large scale screen was performed in Drosophila to determine genes that modify mutant LRRK2 toxicity in both the eye and dopaminergic neurons of the fly. The screen revealed 36 genetic interactors that either suppressed or enhanced LRRK2 induced cell death in the fly. One of these interactors was SCAR (human WAVE-2). Due to the role WAVE-2 is known to have in immune cell phagocytic function, we demonstrate that LRRK2 deficient/G2019S murine myeloid cells have impaired/enhanced phagocytic activity which is correlated with a decrease/increase in WAVE-2 protein, respectively. We furthermore suggest that LRRK2 and WAVE-2 may bind directly and that LRRK2 phosphorylates WAVE-2 to maintain its stability. Finally, as a proof of concept, we constructed a novel animal model of LRRK2 in flies by limiting LRRK2 over expression to central phagocytes of the Drosophila brain. This causes lifespan deficits and motor dysfunction that can be rescued by down-regulation of SCAR. Collectively, this body of work helped create the first germ-line, genetic model of PD that recapitulates nigral loss and elucidated LRRK2 interactors in the fly. Furthermore, we demonstrate that one of these interactors mediated LRRK2’s modulation of phagocytic activity that may contribute to the pathogenesis of PD.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/34860 |
| Date | January 2016 |
| Creators | Marcogliese, Paul C. |
| Contributors | Park, David S. |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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