Genetic analyses of signal transduction pathways involved in neuromuscular excitability and neurodegeneration in Caenorhabtidis elegans

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dc.contributor Marcus, Stevan
dc.contributor O'Donnell, Janis M.
dc.contributor Ramonell, Katrina M.
dc.contributor Caldwell, Kim A.
dc.contributor West, Andrew
dc.contributor.advisor Caldwell, Guy A. Kautu, Bwarenaba B. 2017-03-01T16:36:18Z 2017-03-01T16:36:18Z 2012
dc.identifier.other u0015_0000001_0001108
dc.identifier.other Kautu_alatus_0004D_11360
dc.description Electronic Thesis or Dissertation
dc.description.abstract Signal transduction pathways regulate many cellular and molecular aspects of the brain including neurotransmission and cell survival. Defects in neuronal signaling can lead to a variety of cognitive and affective disorders such as epilepsy and Parkinson's disease. Here, I use a genetically tractable organism, Caenorhabditis elegans (C. elegans), as a model system to study the impact of two canonical signaling pathways on neuronal activity and survival. Using molecular and genetic tools, pharmacological assays, and microscopy techniques, I showed that the canonical Rac GTPase pathway regulates neuronal synchrony in the GABAergic neurons of C. elegans. In our experiments we observed that Rac GTPase mutants exhibited behavioral responses to a GABAA receptor antagonist, pentylenetetrazole. These mutants also exhibited hypersensitivities to an acetylcholinesterase inhibitor, aldicarb, suggesting deficiencies in GABA transmission. Knockdown of selected cytoskeletal genes in Rac hypomorph mutants revealed synergistic interactions, particularly between the dynein motor complex and some members of the canonical Rac-signaling pathway. Examination of the nerve cords of C. elegans revealed that these genetic factors function to regulate vesicle transport in the GABAergic neurons of C. elegans. In my second project, I characterized the role of the heterotrimeric G protein Gɑq in the context of neuronal survival, using a C. elegans model of Parkinson's disease. In this work, we found that activation of Gɑq (EGL-30) can significantly protect the dopaminergic neurons against a human Parkinson's gene, α-synuclein (α-syn). Interestingly, inactivation of downstream effectors of Gαq exacerbated the loss of dopaminergic neurons in the presence of α-syn suggesting that these factors likey function in a common pathway with Gαq to provide protection for the dopaminergic neurons against α-syn-induced toxicity. These data suggest that activation of Gαq signaling pathway can offer protection to the dopaminergic neurons and could be a potential therapeutic target for neurodegenerative diseases like Parkinson's disease. Taken together, my work showed that Rac GTPase signaling pathway controls neuromuscular excitability in C. elegans and Gαq signaling modulates protection of the dopaminergic neurons
dc.format.extent 185 p.
dc.format.medium electronic
dc.format.mimetype application/pdf
dc.language English
dc.language.iso en_US
dc.publisher University of Alabama Libraries
dc.relation.ispartof The University of Alabama Electronic Theses and Dissertations
dc.relation.ispartof The University of Alabama Libraries Digital Collections
dc.relation.hasversion born digital
dc.rights All rights reserved by the author unless otherwise indicated.
dc.subject.other Neurosciences
dc.subject.other Genetics
dc.subject.other Biology
dc.title Genetic analyses of signal transduction pathways involved in neuromuscular excitability and neurodegeneration in Caenorhabtidis elegans
dc.type thesis
dc.type text University of Alabama. Dept. of Biological Sciences Biological Sciences The University of Alabama doctoral Ph.D.

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