Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Neuroscience

Supervisor

Dr. Robert Cumming

Abstract

Mitochondrial dysfunction and elevated reactive oxygen species (ROS) levels are strongly implicated in various neurodegenerative disorders, including Huntington’s disease (HD). Expression of the mutant Huntingtin protein (mHTT) containing an expanded polyglutamine repeat is associated with oxidative stress and toxicity in striatal neurons. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor responsible for regulating expression of a diverse array of antioxidant and cytoprotective genes. Most known Nrf2-activating compounds act through the canonical pathway by mimicking a transient oxidative insult, and treatment effects are short-lived. This study reveals an increase in striatal cell viability, and a reduction in mitochondrial reactive oxygen species (ROS) levels, following treatment with the non-canonical Nrf2-activator 2,3-dimercaptopropanol (DMP). DMP was also found to prevent the formation of Keap1- and Nrf2-positive inclusion bodies. The current study highlights previously unknown intracellular targets of DMP and indicates that this FDA approved compound may have relevance for the treatment of HD and other neurodegenerative disorders.


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