Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biology

Supervisor

Dr. Kathleen Hill

Abstract

Canadian population demographics are shifting to an increase in aged individuals and an increase in the prevalence of neurodegenerative diseases. The post-mitotic nature of most neurons highlights the need to understand the etiology and early mechanisms in neurodegenerative diseases and design targeted therapies. Currently, the etiologies of neurodegeneration are poorly understood but oxidative stress, mitochondrial dysfunction and inflammation are early mechanisms in Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. An anti-aging strategy that can be adapted for use in neurodegeneration is hormesis, where repeated low-level exposures to stressors are beneficial to the cell. Hormesis has demonstrated efficacy in inhibiting hepatocarcinoma in the rat through administration of dietary phenobarbital, which decreases DNA damage, increases DNA repair, and decreases cell proliferation. Given that phenobarbital decreases DNA damage and increases DNA repair, phenobarbital was tested as a hormetic agent in murine neurodegeneration. The harlequin (hq) mouse is a model of mitochondrial dysfunction and oxidative stress with cerebellar degeneration. One-month-old wild type (WT) and hq mice were administered phenobarbital in drinking water at 0, 2 or 4 ppm provided ad libitum, until euthanized at 3, 7, or 10 months of age. Eleven parameters of nocturnal behaviour were examined in WT and hq mice (n=9 to 14). In situ, post-mortem cerebellar tissue sections were examined for neuron loss, cell damage, and reactive oxygen species (ROS) (n=3). In vivo cerebellar mutations were detected using the Big BlueÒ cII mutation assay (n=5 or 6). The transcriptome was analyzed to survey global markers in hq cerebella and response to phenobarbital exposure (n=3). The hq phenotype had no behavioural changes, but had increased neuron loss, limited cell damage, a mutation signature of ROS, and elevated ROS with age. Phenobarbital administration did not prevent cerebellar degeneration in hq mice. Transcriptome data revealed inflammation as an early disease mechanism in hq mice. In hq mice, a down-regulation in the GABAA receptor was found which potentially limits the efficacy of phenobarbital. The hq mouse could benefit from a strategy addressing mitochondrial dysfunction through supplementation with riboflavin, thus increasing activity of complex I of the electron transport chain and increasing ATP production.

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