Parkinson’s Disease (PD) is a devastating progressive neurodegenerative disorder second only to Alzheimer's disease in prevalence. Progression is insidious and PD symptomology manifests when approximately half of the DA neurons projecting from the substantia nigra pars compacta (SNpc) to the striatum are lost. PD is histologically characterized by the presence of intracytoplasmic inclusions primarily composed of hyper-phosphorylated and ubiquinated α-synuclein (SNCA), known as Lewy Bodies. Conserved LB pathology in α-synuclein and LRRK2 mediated disease suggests a common pathological pathway in disease progression. In order to address the potential disease-relevant nexus between these two proteins, we generated transgenic C. elegans lines co-expressing LRRK2 (pan-neuronal) and α-synuclein (dopaminergic neuron specific). We report increased and progressive DA-ergic neuron loss in nematodes co-expressing disease linked mutant LRRK2 and α-synuclein compared to nematode lines expressing only α-synuclein. Also, guided by previous CLR network analysis, we implicated mis-regulation of proteostasis machinery in disease progression by demonstrating differential effects of LRRK2 co-expressed with α-synuclein on macroautophagy in our nematode lines expressing LGG, a marker for autophagic flux. Our studies show overexpression of G2019S LRRK2 inhibits autophagy and accelerates age-related dopaminergic neuron toxicity whereas overexpression of WT LRRK2 does not. Cooverexpression of a-synuclein caused increased inhibition of autophagy and showed an increase in DA-ergic neuron degeneration. Although we have no concrete evidence of interaction, we suggest that LRRK2 demonstrates an agedependent interaction with a-synuclein, which potentiates degeneration of dopaminergic neurons.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/21159 |
| Date | January 2013 |
| Creators | Gowda, Vivek |
| Publisher | Boston University |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | This work is being made available in OpenBU by permission of its author, and is available for research purposes only. All rights are reserved to the author. |
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