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Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy

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(1). We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-e...

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Autores principales: Papadakis, Michalis, Hadley, Gina, Xilouri, Maria, Hoyte, Lisa C., Nagel, Simon, McMenamin, M Mary, Tsaknakis, Grigorios, Watt, Suzanne M., Drakesmith, Cynthia Wright, Chen, Ruoli, Wood, Matthew J A, Zhao, Zonghang, Kessler, Benedikt, Vekrellis, Kostas, Buchan, Alastair M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744134/
https://www.ncbi.nlm.nih.gov/pubmed/23435171
http://dx.doi.org/10.1038/nm.3097
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author Papadakis, Michalis
Hadley, Gina
Xilouri, Maria
Hoyte, Lisa C.
Nagel, Simon
McMenamin, M Mary
Tsaknakis, Grigorios
Watt, Suzanne M.
Drakesmith, Cynthia Wright
Chen, Ruoli
Wood, Matthew J A
Zhao, Zonghang
Kessler, Benedikt
Vekrellis, Kostas
Buchan, Alastair M.
author_facet Papadakis, Michalis
Hadley, Gina
Xilouri, Maria
Hoyte, Lisa C.
Nagel, Simon
McMenamin, M Mary
Tsaknakis, Grigorios
Watt, Suzanne M.
Drakesmith, Cynthia Wright
Chen, Ruoli
Wood, Matthew J A
Zhao, Zonghang
Kessler, Benedikt
Vekrellis, Kostas
Buchan, Alastair M.
author_sort Papadakis, Michalis
collection PubMed
description 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(1). We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia(2) and the tolerance conferred by ischemic preconditioning (IPC)(3), 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.
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spelling pubmed-37441342013-09-01 Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy Papadakis, Michalis Hadley, Gina Xilouri, Maria Hoyte, Lisa C. Nagel, Simon McMenamin, M Mary Tsaknakis, Grigorios Watt, Suzanne M. Drakesmith, Cynthia Wright Chen, Ruoli Wood, Matthew J A Zhao, Zonghang Kessler, Benedikt Vekrellis, Kostas Buchan, Alastair M. Nat Med Article 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(1). We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia(2) and the tolerance conferred by ischemic preconditioning (IPC)(3), 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. 2013-02-24 2013-03 /pmc/articles/PMC3744134/ /pubmed/23435171 http://dx.doi.org/10.1038/nm.3097 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Papadakis, Michalis
Hadley, Gina
Xilouri, Maria
Hoyte, Lisa C.
Nagel, Simon
McMenamin, M Mary
Tsaknakis, Grigorios
Watt, Suzanne M.
Drakesmith, Cynthia Wright
Chen, Ruoli
Wood, Matthew J A
Zhao, Zonghang
Kessler, Benedikt
Vekrellis, Kostas
Buchan, Alastair M.
Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
title Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
title_full Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
title_fullStr Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
title_full_unstemmed Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
title_short Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
title_sort tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744134/
https://www.ncbi.nlm.nih.gov/pubmed/23435171
http://dx.doi.org/10.1038/nm.3097
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