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

https://doi.org/10.1016/j.bbadis.2016.10.009Get rights and content
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Highlights

  • Elevated GABA in aldh5a1−/− mice alters mTOR signaling and autophagy.

  • mTOR inhibition improves dysregulated mTOR signaling in aldh5a1−/− mice.

  • mTOR inhibition improves abnormalities of oxidative stress in aldh5a1−/− mice.

  • Outcomes in adldh5a1−/− mice were optimal with the mTOR inhibitor, Torin 2.

  • Torin 2 is therapeutically relevant in the GABA defect, SSADH deficiency.

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.

Abbreviations

GABA
gamma-aminobutyric acid
Tor 1
Torin 1
Tor 2
Torin 2
SSADH
succinic semialdehyde dehydrogenase
SSADHD
succinic semialdehyde dehydrogenase deficiency
aldh5a1
aldehyde dehydrogenase 5a1 (identical to succinic semialdehyde dehydrogenase)

Keywords

GABA
Succinic semialdehyde dehydrogenase deficiency
mTOR
Torin 1
Torin 2
Oxidative stress

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