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

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 stroke1. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia2 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.

Citation

Papadakis, M., Hadley, G., Xilouri, M., Hoyte, L. C., Nagel, S., McMenamin, M. M., …Buchan, A. M. (2013). Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nature Medicine, 19(3), 351-357. https://doi.org/10.1038/nm.3097

• Journal Article Type: Article
• Acceptance Date: Jan 18, 2013
• Online Publication Date: Feb 24, 2013
• Publication Date: 2013-03
• Deposit Date: Jun 13, 2023
• Journal: Nature Medicine
• Print ISSN: 1078-8956
• Electronic ISSN: 1546-170X
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 19
• Issue: 3
• Pages: 351-357
• DOI: https://doi.org/10.1038/nm.3097
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Medicine