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Behavioral characterization of C. elegans homologs of Parkinson's disease associated genes Knauft, Sara Marie


Parkinson’s disease (PD) is a neurodegenerative disorder of central nervous system affecting more than 10 million people globally. This disease has a strong genetic component with 14% of individuals with PD reporting a first-degree relative with the disease. While genes like PARK2 and PINK1 have been associated with familial early onset PD, LRRK2, DNAJC13, and VPS35 have been linked to idopathic PD. These genes are largely involved in the maintenance of mitochondria or in the quality control via the cellular machinery that degrades unneeded proteins. Mutations in these genes affect the function and survival of particular neurons in parts of the brain that regulate normal movement, balance, and coordination. One endophenotype of PD is abnormal habituation; habituation is a simple form of learning in which repeated stimulation causes a decrement in responding over time. By investigating how these PD associated genes are involved in habituation, we hope to better understand the underlying pathophysiology induced by these genetic differences. In this study mechanosensory habituation was examined in Caenorhabditis elegans (C.elegans; microscopic transparent roundworms) in both wild-type worms and in worms with mutations in homologues of genes implicated in PD. Each strain of mutant worms showed a unique combination of basal characteristics and habituation phenotypes that distinguished them from wild-type worms. The integrity of dopamine neurotransmission was also investigated using the SWIP assay and ON/OFF Food Habituation assay. The C. elegans homologue of the PD gene VPS35, vps-35, an essential component of the retromer complex, was found to display the characteristics of abnormal dopamine signaling and was chosen for additional testing. Experiments using channelrhodopsin confirmed a lower dopamine signaling phenotype, with overexpression and rescue strains of this mutant being created to further explore how this protein affects behavior. These experiments set the groundwork for using C. elegans as a genetic model of PD that can help us better understand this complicated neurological disorder.

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