Evaluating the Brain-enhancing Mitohormesis of N-Propargylglycine, a Suicide Inhibitor of Proline Dehydrogenase, to Offset the Proteotoxic Mechanisms Underlying Neurodegeneration in Huntington’s Disease And Evaluating the Phenotype of a Mutant Pdia3 Knock-in Mouse Line as a Novel Genetic Model of Neurological Disorders
Master of Science
Meredith Protas, PhD
Lisa Ellerby, PhD
Chris Benz, PhD
Huntington’s Disease (HD) is characterized by atrophy of the striatal and cerebral cortical neurons producing a variety of severe, and life-shortening neurologic symptoms including motor dysfunction, cognitive decline, psychiatric disturbances, and weight loss. As with other life-threatening neurodegenerative disorders, HD has no effective treatment capable of preventing or mitigating its underlying hallmark, subcellular and pathogenetic mechanism, that is, proteotoxicity. While it has been suggested that inducing brain mitohormesis might offer a promising therapeutic strategy, to date, no brain-penetrating mitohormesis-inducing agent has yet been identified or tested in any neurodegenerative disease mouse model. Recently, N-propargylglycine (N-PPG) was shown to be a unique suicide inhibitor of the mitochondrial enzyme, proline dehydrogenase (PRODH). PRODH inhibition causes PRODH protein decay while also inducing the mitochondrial unfolded protein response (UPRmt) and is thought to trigger mitohormesis. To test our hypothesis that N-PPG can cross the blood-brain barrier and potentially induce a robust mitohormesis response across multiple brain compartments, an initial experiment was performed using normal B6 mice. N-PPG was administered orally each day at N-PPG doses ranging from 50-200 mg/kg. This exploratory study generated supporting evidence for blood-brain penetration and whole brain mitohormesis induction by N-PPG, compelling further preclinical investigation of N-PPG effects in genetically engineered R6/2 mice that typically die within 15 weeks of life. This thesis project describes three in vivo pilot studies and compares immunoblotting, transcriptomic, metabolomic and behavioral results observed between the control and N-PPG treated wildtype B6 and R6/2 HD mice. These in vivo pilot study results supported the project’s goal of showing that an N-PPG induced brain mitohormesis response could be both robust and durable, lasting long after cessation of N-PPG treatment.
Teramayi, Fadzai, "Evaluating the Brain-enhancing Mitohormesis of N-Propargylglycine, a Suicide Inhibitor of Proline Dehydrogenase, to Offset the Proteotoxic Mechanisms Underlying Neurodegeneration in Huntington’s Disease And Evaluating the Phenotype of a Mutant Pdia3 Knock-in Mouse Line as a Novel Genetic Model of Neurological Disorders" (2022). Natural Sciences and Mathematics | Biological Sciences Master's Theses. 33.
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