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.

Public Health Relevance

We have unmasked in yeast an unexpected role for GABA as an inhibitor of selective autophagy pathways, pexophagy and mitophagy, a process mediated via mTOR activation and associated with oxidative damage. Pilot studies have demonstrated that intervention with the mTOR inhibitor, rapamycin, can significantly mitigate GABA-related pathology, both in yeast and in a murine model of succinic semialdehyde dehydrogenase (SSADH) deficiency. Our project exploits this new role for GABA to develop novel therapeutics for genetic disorders with elevated GABA, as well as providing new insight into the mode(s) of action of antiepileptic medications that elevate GABA, and we predict that our outcomes will significantly advance the knowledge base in both fields.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS085369-01A1
Application #
8769623
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington State University
Department
None
Type
Schools of Pharmacy
DUNS #
City
Pullman
State
WA
Country
United States
Zip Code
99164