Therapeutics of mTOR Signaling in Succinic Semialdehyde Dehydrogenase Deficiency

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DESCRIPTION (provided by applicant): Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1) deficiency remains the most prevalent disorder of GABA (4-aminobutyrate) metabolism, one that is unique in the accretion of two neuromodulators, GABA and GHB (gamma-hydroxybutyric acid). Some 30 years after its discovery, effective pharmacotherapy remains elusive. We recently unmasked in yeast an unexpected role for GABA as an inhibitor of selective autophagy pathways, pexophagy and mitophagy, a process mediated via Sch9 (homolog of mammalian ribosomal S6 kinase 1, S6K1) activation and associated with oxidative damage. Pilot studies have demonstrated that intervention with the mTOR inhibitor, rapamycin, which down-regulates Sch9, can significantly mitigate GABA-related pathology in the murine model, including reducing increased mitochondrial number, improving oxidative stress parameters, and mitigating aberrant cell signaling. Our primary hypothesis posits that therapeutics inhibiting mTOR signaling and/or inducing autophagy will provide an innovative therapeutic approach to heritable disorders featuring GABA elevation, while informing pharmacotherapies that target increased GABA increase in central nervous system (CNS). Aim 1 will examine the physiological, biochemical and cellular effects of mTOR inhibition (rapamycin, torin1, temsirolimus) in aldh5a1-/- mice. Aim 2 will examine the capacity of selected drugs to override disruptions of pexophagy and mitophagy in primary cultures of aldh5a1-/- cells. Our study design will be a 2x2 factorial mixed model for both aims, employing ANOVA with post hoc analyses for statistical analyses. Our rationale for combined cellular and animal studies centers on our prediction that in vitro studies will serve to elucidate GABA-related pathomechanisms, while in vivo studies will outline a more rapid route to clinical intervention. This project will beak new scientific ground on the role of GABA in human biology, accrue preclinical animal data that will pave the way for novel therapeutics in disorders with elevated CNS GABA, and provide new insights on the use of selected antiepileptics whose pharmacological objective is to increase GABA. We are evaluating rational therapies based upon our pilot studies, but these therapies cannot be piloted in humans without additional preclinical data. Our laboratory has already spring-boarded preclinical animal data using taurine and SGS-742 into human clinical trials in SSADH deficiency, underscoring the potential for success in the current project.