PMID- 31636454 OWN - NLM STAT- MEDLINE DCOM- 20200120 LR - 20231113 IS - 1546-170X (Electronic) IS - 1078-8956 (Print) IS - 1078-8956 (Linking) VI - 25 IP - 11 DP - 2019 Nov TI - Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency. PG - 1684-1690 LID - 10.1038/s41591-019-0608-y [doi] AB - Dysregulation of the mammalian target of rapamycin (mTOR) signaling, which is mediated by two structurally and functionally distinct complexes, mTORC1 and mTORC2, has been implicated in several neurological disorders(1-3). Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability(2,4,5). It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (for example, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis(1,2,4,6,7). Using molecular genetics, we unexpectedly found that genetic deletion of mTORC2 (but not mTORC1) activity prolonged lifespan, suppressed seizures, rescued ASD-like behaviors and long-term memory, and normalized metabolic changes in the brain of mice lacking Pten. In a more therapeutically oriented approach, we found that administration of an antisense oligonucleotide (ASO) targeting mTORC2's defining component Rictor specifically inhibits mTORC2 activity and reverses the behavioral and neurophysiological abnormalities in adolescent Pten-deficient mice. Collectively, our findings indicate that mTORC2 is the major driver underlying the neuropathophysiology associated with Pten-deficiency, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where mTOR signaling is dysregulated. FAU - Chen, Chien-Ju AU - Chen CJ AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Sgritta, Martina AU - Sgritta M AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Mays, Jacqunae AU - Mays J AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Zhou, Hongyi AU - Zhou H AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Lucero, Rocco AU - Lucero R AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. AD - Department of Neurology, Baylor College of Medicine, Houston, TX, USA. FAU - Park, Jin AU - Park J AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Wang, I-Ching AU - Wang IC AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Park, Jun Hyoung AU - Park JH AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. FAU - Kaipparettu, Benny Abraham AU - Kaipparettu BA AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. AD - Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. FAU - Stoica, Loredana AU - Stoica L AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Jafar-Nejad, Paymaan AU - Jafar-Nejad P AD - Ionis Pharmaceuticals, Carlsbad, CA, USA. FAU - Rigo, Frank AU - Rigo F AD - Ionis Pharmaceuticals, Carlsbad, CA, USA. FAU - Chin, Jeannie AU - Chin J AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. FAU - Noebels, Jeffrey L AU - Noebels JL AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. AD - Department of Neurology, Baylor College of Medicine, Houston, TX, USA. FAU - Costa-Mattioli, Mauro AU - Costa-Mattioli M AUID- ORCID: 0000-0002-9809-4732 AD - Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. costamat@bcm.edu. AD - Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA. costamat@bcm.edu. AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. costamat@bcm.edu. LA - eng GR - R01 NS085171/NS/NINDS NIH HHS/United States GR - R01 NS076708/NS/NINDS NIH HHS/United States GR - R01 NS086965/NS/NINDS NIH HHS/United States GR - R01 NS029709/NS/NINDS NIH HHS/United States GR - R01 MH096816/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20191021 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (Oligonucleotides, Antisense) RN - 0 (Rapamycin-Insensitive Companion of mTOR Protein) RN - 0 (Tsc1 protein, mouse) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (rictor protein, mouse) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) RN - EC 3.1.3.67 (Pten protein, mouse) SB - IM CIN - Neuron. 2019 Dec 18;104(6):1032-1033. PMID: 31951535 CIN - Epilepsy Curr. 2020 Mar;20(2):116-117. PMID: 32100554 MH - Animals MH - Brain/metabolism/pathology MH - Disease Models, Animal MH - Humans MH - Loss of Function Mutation/genetics MH - Mechanistic Target of Rapamycin Complex 1/genetics MH - Mechanistic Target of Rapamycin Complex 2/*genetics MH - Mice MH - Mice, Knockout MH - Nervous System Diseases/*genetics/metabolism/pathology MH - Oligonucleotides, Antisense/genetics/pharmacology MH - PTEN Phosphohydrolase/deficiency/*genetics MH - Rapamycin-Insensitive Companion of mTOR Protein/antagonists & inhibitors/genetics MH - TOR Serine-Threonine Kinases/*genetics MH - Tuberous Sclerosis Complex 1 Protein/genetics PMC - PMC7082835 MID - NIHMS1539623 EDAT- 2019/10/23 06:00 MHDA- 2020/01/21 06:00 PMCR- 2020/04/21 CRDT- 2019/10/23 06:00 PHST- 2019/02/22 00:00 [received] PHST- 2019/09/10 00:00 [accepted] PHST- 2019/10/23 06:00 [pubmed] PHST- 2020/01/21 06:00 [medline] PHST- 2019/10/23 06:00 [entrez] PHST- 2020/04/21 00:00 [pmc-release] AID - 10.1038/s41591-019-0608-y [pii] AID - 10.1038/s41591-019-0608-y [doi] PST - ppublish SO - Nat Med. 2019 Nov;25(11):1684-1690. doi: 10.1038/s41591-019-0608-y. Epub 2019 Oct 21.