Thursday, 14 March 2013

Staying Alive in a Recession: Hamartin and Autophagy

mTOR (mammalian target of rapamycin) is a profligate protein that activates pathways leading to increased protein synthesis, cell growth and proliferation, which is all well and good in those boom periods when neurons are well-supplied with oxygen and nutrients. However, following ischaemic stroke, neurons are plunged into a recession, deprived of oxygen and energy. Parts of the brain which maintain mTOR activity post-stroke (e.g. the CA1 region of the hippocampus) are essentially engaging in ruinous, unsustainable deficit spending, leading to their eventual demise. However, those parts of the brain that are able to tamp down mTOR activity post-stroke (e.g. the CA3 region) can impose austerity measures, enabling them to reduce protein synthesis and recycle existing proteins through protective autophagy, letting them ride out the recession until blood flow is restored.

How can we take advantage of this endogenous neuroprotective mechanism? Enter hamartin (TSC1). Part of the tuberous sclerosis complex, hamartin is a tumour suppressor whose absence leads to proliferation of multi-organ benign tumours. It operates by inhibiting the action of mTOR (via a GTPase-activating protein activity on Rheb, an upstream protein in the mTOR pathway). Hamartin expression is significantly induced in the CA3 region, but not the CA1, following ischaemia, allowing CA3 cells to downregulate mTOR activity and impose the austerity measures, reduced protein synthesis and autophagy, crucial to their survival. The hamartin pathway offers an exciting potential target for exogenous neuroprotective therapy in stroke.

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