Date of Award
Daniel A. Linseman, Ph.D.
Cdc42, Amyotrophic Lateral Sclerosis (ALS), Rho GTPase, Neurodegenerative Disease, Therapies
Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's and Parkinson's disease are caused by a progressive and aberrant destruction of neurons in the brain and spinal cord. These disorders lack effective long term treatments, and existing options focus primarily on either delaying disease onset or alleviating symptomology. Dysregulated programmed cell death, known as apoptosis, is one of the most significant contributors to neurodegeneration, and is controlled by a number of different factors. Rho GTPases are a protein class with recognized importance in proper neuronal development and migration, and have more recently emerged as regulators of apoptosis and neuronal survival. Here, we investigated the role of Rho GTPase family member Cdc42 and its downstream effectors in neuronal survival and apoptosis. Our goal was to determine whether a Cdc42 signaling pathway contributes to the survival of neurons subjected to arduous growth conditions, simulating pathophysiological stress endured during neurodegeneration. We initially induced apoptosis in rat cerebellar granule neurons (CGNs) by removing both growth factor-containing serum and depolarizing potassium from the cell media. We then utilized both chemical inhibitors and adenoviral Cdc42 shRNA to block the function of Cdc42 or its downstream effectors in this stressful growth environment. Our in vitro studies demonstrate that functional inhibition of Cdc42 or two of its downstream targets (ACK-1 and PAK) did significantly sensitize neurons to cell death under duress. Our results advocate a pro-survival role for Cdc42 in neurons, and propose that it could be a potential therapeutic target for decelerating the advancement of neurodegenerative disease.
Punessen, Noelle Christine, "Small Rho GTPase Family Member Cdc42 and its Role in Neuronal Survival and Apoptosis" (2017). Electronic Theses and Dissertations. 1337.
Received from ProQuest
Noelle Christine Punessen
Biology, Molecular Biology