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. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-esta...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2013
|
| _version_ | 1797055254831824896 |
|---|---|
| author | Papadakis, M Hadley, G Xilouri, M Hoyte, L Nagel, S Mcmenamin, M Tsaknakis, G Watt, S Drakesmith, C Chen, R Wood, M Zhao, Z Kessler, B Vekrellis, K Buchan, A |
| author_facet | Papadakis, M Hadley, G Xilouri, M Hoyte, L Nagel, S Mcmenamin, M Tsaknakis, G Watt, S Drakesmith, C Chen, R Wood, M Zhao, Z Kessler, B Vekrellis, K Buchan, A |
| author_sort | Papadakis, M |
| collection | OXFORD |
| 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. 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. Copyright © 2013 Nature America, Inc. |
| first_indexed | 2024-03-06T19:08:04Z |
| format | Journal article |
| id | oxford-uuid:15d65104-c66e-475f-8ca5-67e5bac2e79f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:08:04Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:15d65104-c66e-475f-8ca5-67e5bac2e79f2022-03-26T10:27:44ZTsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:15d65104-c66e-475f-8ca5-67e5bac2e79fEnglishSymplectic Elements at Oxford2013Papadakis, MHadley, GXilouri, MHoyte, LNagel, SMcmenamin, MTsaknakis, GWatt, SDrakesmith, CChen, RWood, MZhao, ZKessler, BVekrellis, KBuchan, APrevious 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. Copyright © 2013 Nature America, Inc. |
| spellingShingle | Papadakis, M Hadley, G Xilouri, M Hoyte, L Nagel, S Mcmenamin, M Tsaknakis, G Watt, S Drakesmith, C Chen, R Wood, M Zhao, Z Kessler, B Vekrellis, K Buchan, A 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 |
| work_keys_str_mv | AT papadakism tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT hadleyg tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT xilourim tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT hoytel tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT nagels tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT mcmenaminm tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT tsaknakisg tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT watts tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT drakesmithc tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT chenr tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT woodm tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT zhaoz tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT kesslerb tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT vekrellisk tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy AT buchana tsc1hamartinconfersneuroprotectionagainstischemiabyinducingautophagy |