title: 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 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.
authors: 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.
authors: Kara R
authors: KR
authors: Vogel
authors: 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.
authors: Garrett R
authors: GR
authors: Ainslie
authors: 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.
authors: K Michael
authors: KM
authors: Gibson
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002658:Developmental Disabilities / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D047928:Premature Birth / Q000401:mortality*; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D009025:Morpholines; D011743:Pyrimidines; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C541932:Ku 0063794; D050644:Succinate-Semialdehyde Dehydrogenase; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus