mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

Abstract

Recent studies have identified a role for supraphysiological GABA in the regulation of mTOR (mechanistic target of rapamycin), a protein kinase with pleiotropic roles in cellular development and homeostasis, including integration of growth factors and nutrient sensing, and synaptic input in neurons (Lakhani et al 2014; Vogel et al 2015). Aldehyde dehydrogenase 5a1-deficient (aldh5a1−/−) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA that disrupts mitophagy and increases mitochondria number with enhanced oxidant stress. Treatment with the mTOR inhibitor, rapamycin, significantly attenuates these GABA-related anomalies. We extend those studies through characterization of additional rapalog agents including temsirolimus, dual mTOR inhibitors (torin 1 and 2 (Tor1/ Tor 2), Ku-0063794, and XL-765), as well as mTOR-independent autophagy inducers (trehalose, tat-Beclin 1, FK-506, and NF-449) in aldh5a1−/− mice. Rapamycin, Tor1, and Tor2 rescued these mice from premature lethality associated with status epilepticus. XL-765 extended lifespan significantly and induced weight gain in aldh5a1−/− mice; untreated aldh5a1−/− mice fail to increase body mass. Expression profiling of animals rescued with Tor1/Tor2 and XL-765 revealed multiple instances of pharmacological compensation and/or correction of GABAergic and glutamatergic receptors, GABA/glutamate transporters, and GABA/glutamate-associated proteins, with Tor2 and XL-765 showing optimal outcomes. Our studies lay the groundwork for further evaluation of mTOR inhibitors in aldh5a1−/− mice, with therapeutic ramifications for heritable disorders of GABA and glutamate neurotransmission.

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

“…This has been confirmed by a number of investigators in the knockout mouse model (Gibson et al 2006; Latini et al 2007; Vogel et al, in press). Moreover, Sauer and colleagues (2007) extended these findings to demonstrate significant disruptions of enzyme complexes involved in mitochondrial oxidative metabolism in brain tissues derived from SSADHD knockout mice, which lends additional credence to the potential disruptive nature of DHHA in mitochondrial metabolism.…”

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

“…Further, we examined the capacity of newer generation drugs (Tor 1, Tor 2) that inhibit mTOR signaling to improve mRNA levels corresponding to these genes (Tables 1, 2). Additional rationale for examining the molecular aspects (mRNA levels) related to Tor 1 and Tor 2 intervention in aldh5a1 −/− mice derived from our finding that these agents are capable of significantly extending the lifespan of these mice [32]. …”

“…Armed with the preceding metabolic evidence for oxidative stress in aldh5a1 −/− mice, we opted to pursue a global assessment of both mTOR signaling and oxidative stress employing gene expression analysis for mRNA levels. Our rationale for these studies centered on earlier work with GABA, mTOR and oxidative stress [1, 13, 32], in which we showed that elevated GABA, acting via mTOR, induced accumulation of mitochondria and enhanced oxidative stress. The finding that rapamycin could mitigate these effects led us to investigate newer generation mTOR inhibitors.…”

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

“…Several publications have highlighted alterations in GABAergic neurotransmission in SSADHD (Pearl et al 2009; Reis et al 2012; Buzzi et al 2006), both in the orthologue mouse model and patients, and it may be reasonable to assume that high levels of GABA and GHB during ontogeny induces an altered balance between GABAergic/GHBergic neurotransmission with that of excitatory glutamatergic neurotransmission (Jansen et al 2008; Vogel et al 2016; Talaei et al 2016). Our prediction is that as levels of GABA and GHB fall with age, this balance is likely disrupted and correlates with neuropsychiatric morbidity in patients.…”