title: Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy.
abstract: Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.
authors: Laboratory of Cerebral Ischemia, Acute Stroke Programme, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors: Michalis
authors: M
authors: Papadakis
authors: Gina
authors: G
authors: Hadley
authors: Maria
authors: M
authors: Xilouri
authors: Lisa C
authors: LC
authors: Hoyte
authors: Simon
authors: S
authors: Nagel
authors: M Mary
authors: MM
authors: McMenamin
authors: Grigorios
authors: G
authors: Tsaknakis
authors: Suzanne M
authors: SM
authors: Watt
authors: Cynthia Wright
authors: CW
authors: Drakesmith
authors: Ruoli
authors: R
authors: Chen
authors: Matthew J A
authors: MJ
authors: Wood
authors: Zonghang
authors: Z
authors: Zhao
authors: Benedikt
authors: B
authors: Kessler
authors: Kostas
authors: K
authors: Vekrellis
authors: Alastair M
authors: AM
authors: Buchan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000502:physiology*; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D000860:Hypoxia; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000517:prevention & control*; D019194:Ischemic Preconditioning; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D018696:Neuroprotective Agents / Q000378:metabolism*; D016548:Prosencephalon / Q000098:blood supply / Q000293:injuries; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D018696:Neuroprotective Agents; D011506:Proteins; D034741:RNA, Small Interfering; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C025946:3-methyladenine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000225:Adenine; D020123:Sirolimus