PMID- 27518770 OWN - NLM STAT- MEDLINE DCOM- 20171205 LR - 20211204 IS - 1573-2665 (Electronic) IS - 0141-8955 (Print) IS - 0141-8955 (Linking) VI - 39 IP - 6 DP - 2016 Nov TI - mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. PG - 877-886 AB - Recent studies have identified a role for supraphysiological gamma-aminobutyric acid (GABA) in the regulation of mechanistic target of rapamycin (mTOR), 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 rapamycin analog (rapalog) agents including temsirolimus, dual mTOR inhibitors [Torin 1 and 2 (Tor 1/ Tor 2), Ku-0063794, and XL-765], as well as mTOR-independent autophagy inducers [trehalose, tat-Beclin 1, tacrolimus (FK-506), and NF-449) in aldh5a1 (-/-) mice. Rapamycin, Tor 1, and Tor 2 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 failed to increase body mass. Expression profiling of animals rescued with Tor 1/Tor 2 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 Tor 2 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. FAU - Vogel, Kara R AU - Vogel KR AD - Division of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Pharmaceutical and Basic Sciences Building Room 347, 412 E. Spokane Falls Blvd, Spokane, WA, 99202, USA. k.vogel@wsu.edu. FAU - Ainslie, Garrett R AU - Ainslie GR AD - Division of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Pharmaceutical and Basic Sciences Building Room 347, 412 E. Spokane Falls Blvd, Spokane, WA, 99202, USA. FAU - Gibson, K Michael AU - Gibson KM AD - Division of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Pharmaceutical and Basic Sciences Building Room 347, 412 E. Spokane Falls Blvd, Spokane, WA, 99202, USA. LA - eng GR - R21 NS085369/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20160812 PL - United States TA - J Inherit Metab Dis JT - Journal of inherited metabolic disease JID - 7910918 RN - 0 (Morpholines) RN - 0 (Pyrimidines) RN - 0 (Quinoxalines) RN - 0 (Sulfonamides) RN - 0 (XL765) RN - 3KX376GY7L (Glutamic Acid) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 81HJG228AB (Ku 0063794) RN - EC 1.2.1.24 (Succinate-Semialdehyde Dehydrogenase) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) RN - succinic semialdehyde dehydrogenase deficiency SB - IM MH - Amino Acid Metabolism, Inborn Errors/*drug therapy/metabolism MH - Animals MH - Developmental Disabilities/*drug therapy/metabolism MH - Disease Models, Animal MH - Glutamic Acid/*metabolism MH - Mice MH - Morpholines/pharmacology MH - Neurons/drug effects/metabolism MH - Premature Birth/*mortality MH - Pyrimidines/pharmacology MH - Quinoxalines/pharmacology MH - Sirolimus/pharmacology MH - Succinate-Semialdehyde Dehydrogenase/*deficiency/*metabolism MH - Sulfonamides/pharmacology MH - Synaptic Transmission/drug effects MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Transcription, Genetic/*drug effects MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC5114712 MID - NIHMS810410 COIS- Kara R. Vogel declares that she has no conflict of interest. Garrett R. Ainslie declares that he has no conflict of interest K. Michael Gibson declares that he has no conflict of interest. EDAT- 2016/08/16 06:00 MHDA- 2017/12/06 06:00 PMCR- 2017/11/01 CRDT- 2016/08/13 06:00 PHST- 2016/05/06 00:00 [received] PHST- 2016/06/21 00:00 [accepted] PHST- 2016/06/15 00:00 [revised] PHST- 2016/08/16 06:00 [pubmed] PHST- 2017/12/06 06:00 [medline] PHST- 2016/08/13 06:00 [entrez] PHST- 2017/11/01 00:00 [pmc-release] AID - 10.1007/s10545-016-9959-4 [pii] AID - 10.1007/s10545-016-9959-4 [doi] PST - ppublish SO - J Inherit Metab Dis. 2016 Nov;39(6):877-886. doi: 10.1007/s10545-016-9959-4. Epub 2016 Aug 12.