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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Biological Sciences
First Advisor
Miriam L. Greenberg
Abstract
Inositol is an essential component of cellular functions. Importantly, de novo synthesis of inositol accounts for nearly half of the inositol found in the brain. Valproate, a drug used to treat neurological disorders such as epilepsy, bipolar disorder, and migraines, induces inositol depletion by preventing its synthesis, which is a hypothesized therapeutic mechanism for its mood stabilizing effect. However, the mechanism by which this occurs is not known, but it is likely due to activation of cellular mechanisms that downregulate inositol synthesis. Shortly after treating yeast cells with valproate, there is reduced expression of the protein that facilitates the rate-limiting step of inositol synthesis, myo-inositol-3-phosphate synthase (MIPS). This is a result of the Henry regulatory circuit transcriptionally repressing the INO1 gene that encodes MIPS. Although INO1 transcription eventually recovers, MIPS protein levels remain lower than control levels. Most likely, this is a consequence of another outcome of valproate treatment which rapidly activates Snf1 and inhibits TORC1. These master metabolic regulators control cellular metabolism and the actions of valproate induce catabolism, which reduces the rate of translation and protein synthesis. Therefore, the pleiotropic effects of VPA bring about the initial decrease in MIPS protein levels not only by repressing INO1 transcription but also by preventing its recovery by downregulating translation. These various and independent effects of valproate likely underlie the complex mechanisms that collectively induce the therapeutic effects of valproate treatment.
Recommended Citation
Case, Kendall, "Valproate-Induced Inositol Depletion Is A Consequence Of Reduced Mips Expression Mediated By The Henry Regulatory Circuit" (2024). Wayne State University Dissertations. 3989.
https://digitalcommons.wayne.edu/oa_dissertations/3989
