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

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 measured 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.

Correlation of blood biomarkers with age informs pathomechanisms in succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

“…Although GABA levels have been effectively quantified in platelets isolated from whole blood (Kowa et al 1992), we opted for isolation of plasma since an objective was to determine if total GABA levels might be elevated in this compartment and potentially inform GABA concentrations in whole bloodspots for eventual newborn screening of SSADHD. Moreover, since we have recently demonstrated that both GHB and GABA are significantly elevated in brain and peripheral organs (kidney, liver) of SSADH-deficient mice (Vogel et al, in revision), we assume that peripheral GABA metabolism mimics the pathway of metabolism shown in brain. The latter underscores the utility of measuring these biomarkers in peripheral tissues (plasma, red blood cells) as a surrogate for brain, or even cerebrospinal fluid, measurements.…”

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…Nutrient starvation is associated with dissociation of the inactive mTORC1 from the lysosomes, resulting in increased autophagy. Thus, activation of mTOR by GABA is likely to exacerbate the accumulation of aberrant mitochondria in SSADH-D by inhibiting mitophagy, suggesting that mTOR inhibition may exhibit therapeutic potential in SSADH-D. Vogel and coworkers analyzed the effect of various mTORC inhibitors in SSADH knockout mice [78,79]. They showed that the lifespan of the mice can be extended by dual inhibitors of mTORC1 and mTORC2, Torin 2, and XL-765 [79].…”

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…They showed that the lifespan of the mice can be extended by dual inhibitors of mTORC1 and mTORC2, Torin 2 and XL-765 [65]. In addition, the mTOR-independent autophagy inducing peptide tat-Beclin 1 [66] also prevented the early lethality in these mice [65]. These findings suggest that inhibition of mTOR activity and/or induction of autophagy may exhibit therapeutic potential in SSADH-D.…”

“…Nutrient starvation is associated with dissociation of the inactive mTORC1 from the lysosomes, resulting in increased autophagy. Thus, activation of mTOR by GABA is likely to exacerbate the accumulation of aberrant mitochondria in SSADH-D by inhibiting mitophagy, suggesting that mTOR inhibition may exhibit therapeutic potential in SSADH-D. Vogel and coworkers have analyzed the effect of various mTORC inhibitors in the SSADH knockout mice [64,65]. They showed that the lifespan of the mice can be extended by dual inhibitors of mTORC1 and mTORC2, Torin 2 and XL-765 [65].…”

“…Thus, activation of mTOR by GABA is likely to exacerbate the accumulation of aberrant mitochondria in SSADH-D by inhibiting mitophagy, suggesting that mTOR inhibition may exhibit therapeutic potential in SSADH-D. Vogel and coworkers have analyzed the effect of various mTORC inhibitors in the SSADH knockout mice [64,65]. They showed that the lifespan of the mice can be extended by dual inhibitors of mTORC1 and mTORC2, Torin 2 and XL-765 [65]. In addition, the mTOR-independent autophagy inducing peptide tat-Beclin 1 [66] also prevented the early lethality in these mice [65].…”