Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):33-42. doi: 10.1016/j.bbadis.2016.10.009. Epub 2016 Oct 17.

Abstract

Aldehyde dehydrogenase 5a1-deficient (aldh5a1-/-) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis that aldh5a1-/- mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR. We observed that multiple metabolites associated with GABA metabolism (γ-hydroxybutyrate, succinic semialdehyde, D-2-hydroxyglutarate, 4,5-dihydrohexanoate) and oxidative stress were significantly increased in multiple tissues derived from aldh5a1-/- mice. These metabolic perturbations were associated with decreased levels of reduced glutathione (GSH) in brain and liver of aldh5a1-/- mice, as well as increased levels of adducts of the lipid peroxidation by-product, 4-hydroxy-2-nonenal (4-HNE). Decreased liver mRNA levels for multiple genes associated with mTOR signaling and oxidative stress parameters were detected in aldh5a1-/- mice, and several were significantly improved with the administration of mTOR inhibitors (Torin 1/Torin 2). Western blot analysis of selected proteins corresponding to oxidative stress transcripts (glutathione transferase, superoxide dismutase, peroxiredoxin 1) confirmed gene expression findings. Our data provide additional preclinical evidence for the potential therapeutic efficacy of mTOR inhibitors in SSADHD.

Keywords: GABA; Oxidative stress; Succinic semialdehyde dehydrogenase deficiency; Torin 1; Torin 2; mTOR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / drug therapy*
  • Amino Acid Metabolism, Inborn Errors / genetics
  • Amino Acid Metabolism, Inborn Errors / metabolism*
  • Animals
  • Developmental Disabilities / drug therapy*
  • Developmental Disabilities / genetics
  • Developmental Disabilities / metabolism*
  • Disease Models, Animal
  • Female
  • Gene Deletion*
  • Glutathione / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Naphthyridines / pharmacology
  • Oxidative Stress / drug effects
  • Signal Transduction / drug effects
  • Succinate-Semialdehyde Dehydrogenase / deficiency*
  • Succinate-Semialdehyde Dehydrogenase / genetics
  • Succinate-Semialdehyde Dehydrogenase / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcriptome / drug effects
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Naphthyridines
  • gamma-Aminobutyric Acid
  • Aldh5a1 protein, mouse
  • Succinate-Semialdehyde Dehydrogenase
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Glutathione

Supplementary concepts

  • succinic semialdehyde dehydrogenase deficiency