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 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.

Importance of Preclinical Research in the Development of Neuroprotective Strategies for Ischemic Stroke

“…24 Hamartin upregulation was also associated with protection achieved through preconditioning of the otherwise vulnerable CA1 cells. 24 Hamartin associates with tuberin to form the tuberous sclerosis complex, which acts as a tumor suppressor by inhibiting the mammalian target of rapamycin (mTOR) via its GTPase-activating protein activity toward Rheb. 37 A possible mechanism by which hamartin upregulation may afford neuroprotection is recycling of proteins through productive autophagy.…”

“…Both 4-vessel occlusion and 2-vessel occlusion with hypotension models of global forebrain ischemia cause neuronal death in vulnerable brain areas (eg, CA1 of the hippocampus 11,24 ) while sparing resistant areas (eg, the dentate gyrus and CA3). This differential response allows us to investigate the molecular determinants of either resistance or vulnerability in a given region, thus potentially uncovering endogenous neuroprotective strategies.…”

“…This differential response allows us to investigate the molecular determinants of either resistance or vulnerability in a given region, thus potentially uncovering endogenous neuroprotective strategies. 24 The main caveat of global ischemia is that its extent, severity, and duration do not match clinical ischemic stroke; instead, it replicates cardiac arrest. 22 Focal ischemia models typically involve the occlusion of one of the major cerebral arteries, typically the middle cerebral artery, using mechanical means, vasoconstrictors, or thrombi.…”

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations

“…TSC1 protein has many binding partners in addition to TSC2, and is essential for mouse embryonic development [22][23][24] . Recently, it has been shown that TSC1 has critical roles in neurodevelopment and neurological diseases, immune diseases, diabetes, autophagy and DNA repair [25][26][27][28] . Similar to the signalling mechanism in mammalian cells, the TSC1-TSC2 complex in S. pombe also regulates the TOR kinase activity, and has a role in amino-acid uptake from the environment and amino-acid homeostasis [29][30][31] .…”

Phaseic Acid, an Endogenous and Reversible Inhibitor of Glutamate Receptors in Mouse Brain

“…Despite of decades of effort trying to find ways to protect neurons against ischemic insult, no clinical effective drugs are available. It is known that brain can indeed launch an internal protective response against ischemic insult, such as activating autophagy machinery (8). However, in general, the brain's endogenous protective mechanisms against cerebral ischemia remain not well understood.…”