title: Prolonging the survival of Tsc2 conditional knockout mice by glutamine supplementation.
abstract: The genetic disease tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by loss of function mutations in either TSC1 (hamartin) or TSC2 (tuberin), which serve as negative regulators of mechanistic target of rapamycin complex 1 (mTORC1) activity. TSC patients exhibit developmental brain abnormalities and tuber formations that are associated with neuropsychological and neurocognitive impairments, seizures and premature death. Mechanistically, TSC1 and TSC2 loss of function mutations result in abnormally high mTORC1 activity. Thus, the development of a strategy to inhibit abnormally high mTORC1 activity may have therapeutic value in the treatment of TSC. mTORC1 is a master regulator of growth processes, and its activity can be reduced by withdrawal of growth factors, decreased energy availability, and by the immunosuppressant rapamycin. Recently, glutamine has been shown to alter mTORC1 activity in a TSC1-TSC2 independent manner in cells cultured under amino acid- and serum-deprived conditions. Since starvation culture conditions are not physiologically relevant, we examined if glutamine can regulate mTORC1 in non-deprived cells and in a murine model of TSC. Our results show that glutamine can reduce phosphorylation of S6 and S6 kinase, surrogate indicators of mTORC1 activity, in both deprived and non-deprived cells, although higher concentrations were required for non-deprived cultures. When administered orally to TSC2 knockout mice, glutamine reduced S6 phosphorylation in the brain and significantly prolonged their lifespan. Taken together, these results suggest that glutamine supplementation can be used as a potential treatment for TSC.
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston, TX 77225, USA.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rozas
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston, TX 77225, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Redell
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
authors.forename: James
authors.initials: J
authors.lastname: McKenna
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston, TX 77225, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Moore
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston, TX 77225, USA. Electronic address: p.dash@uth.tmc.edu.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D005973:Glutamine / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D005973:Glutamine; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases
keywords: Forebrain-specific Tsc2 Knock-out; Hippocampus; Kaplan–Meier; Mammalian target of rapamycin; mTOR overactivation