Investigation of Environmental and Genetic Risk Factors in the Development of Parkinson's Disease Utilizing the Model Organism

Download or read book Investigation of Environmental and Genetic Risk Factors in the Development of Parkinson's Disease Utilizing the Model Organism written by Hanna Kim and published by . This book was released on 2018 with total page 352 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the main features of Parkinson's disease (PD) is the loss of nigrostriatal dopaminergic (DA) neurons in the presence of alpha-synuclein (a-syn) inclusions known as Lewy Bodies. Over 90% of PD cases are sporadic while the remaining 5-10% have been associated with a genetic cause. It is thought that the environment, or a combination of environment and genetic factors, might lead to the loss of DA neurons in most sporadic PD cases. Increasing evidence suggests that mitochondrial dysfunction plays a central role in the development of DA neurodegeneration where both environmental and genetic contributors can be a source for mitochondrial dysfunction. Neurons are highly vulnerable to environmental and genetic factors that contribute to mitochondrial damage due to their high energy demands. Therefore, when these organelles are damaged, it can lead to disruption of mitochondrial homeostatic mechanisms, such as mitochondrial dynamics, autophagy, and cell death pathways, which can ultimately manifest as DA neurodegeneration. Using genetics and cell biology in Caenorhabditis elegans (C. elegans) as a PD animal model, we demonstrated mechanistic insights of gene by environmental interaction on mitochondrial homeostatic mechanisms in response to a bacterial secondary metabolite from a common soil bacteria, Streptomyces venezuelae (S. ven). We found that the S. ven metabolite disrupts protein homeostasis through impairment of the ubiquitin proteasome system, mitophagy alteration, and glutathione homeostasis interruption. Furthermore, metabolite exposure causes an imbalance in mitochondrial fission and fusion that results in mitochondrial fragmentation and mitochondrial DNA damage, leading to DA neurodegeneration. Acknowledging that not all DA neuronal vulnerability comes from environmental exposures, the role of a small GTPase, RAC1 (ced-10 in C. elegans), was investigated. This protein normally functions in cytoskeletal extension and the phagocytosis of dead cells or engulfment; here, it was found to maintain DA neurons in the presence of a-syn in both C. elegans and human cell culture models. Specifically, a ced-10/Rac1 mutant, or depletion of ced-10 by RNAi, caused increase of a-syn accumulation and DA neurodegeneration. Overexpression of ced-10/Rac1 reduced ced-10 depletion in C. elegans as well as in cell lines. Taken together, experimental findings with both gene backgrounds (Rac1/ced-10) and environmental exposures (S. ven) and provide insight into mechanisms underlying DA neuron cell death and the pathogenesis of PD.