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)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
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
2014-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington State University
Department
Type
Schools of Pharmacy
DUNS #
City
Pullman
State
WA
Country
United States
Zip Code
99164
Vogel, Kara R; Ainslie, Garrett R; Walters, Dana C et al. (2018) Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies. J Inherit Metab Dis 41:699-708
Vogel, K R; Ainslie, G R; Jansen, E E W et al. (2017) Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. Biochim Biophys Acta Mol Basis Dis 1863:33-42
Vogel, Kara R; Ainslie, Garrett R; Schmidt, Michelle A et al. (2017) mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice. Pediatr Neurol 66:44-52.e1
Vogel, K R; Ainslie, G R; Pearl, P L et al. (2017) Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin-associated ocular toxicity? Clin Pharmacol Ther 101:458-461
Vogel, Kara R; Ainslie, Garrett R; Gibson, K Michael (2016) mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. J Inherit Metab Dis 39:877-886
Malaspina, P; Roullet, J-B; Pearl, P L et al. (2016) Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Neurochem Int 99:72-84
Vogel, Kara R; Ainslie, Garrett R; Phillips, Brian et al. (2015) Physiological Competition of Brain Phenylalanine Accretion: Initial Pharmacokinetic Analyses of Aminoisobutyric and Methylaminoisobutyric Acids in Pahenu2-/- Mice. Mol Genet Metab Rep 3:80-87