Article Text
Abstract
Background Huntington's disease (HD) is a neurodegenerative disorder induced by cell toxicity caused by polyglutamine (polyQ) expansion in the N-terminal region of huntingtin (Htt). We use C elegans expressing 128Q in neurons to screen for genes that modulate the early phases (neuron dysfunction) of mutant polyQ cytotoxicity. Using these worms we have shown previously the neuroprotective roles of sirtuin sir-2.1/SIRT1 and daf-16/FoxO. Here, we report that AMPK, an energy sensor involved health span extension in worms and mammals, has neuroprotective effects against the early phases of mutant polyQ cytotocity.
Aims Here we characterise AMPK in the context of neuronal dysfunction/cell vunerability caused by mutant forms of htt in models of HD.
Methods We studied the function of AMPK in C elegans, and its potential interaction with neuroprotective genes (ie, daf-16/FOXO and sir-2.1/Sirtuin), by using mutants combined with transgenesis and drugs. We then confirmed the protective role of mammalian AMPK in striatal cells derived from htt knock-in mice. Finally we tested for the effect of AMPK activation in mice that express mutant htt.
Results By using genetic analysis in worms, we show that AMPK is required for protection against neuron dysfunction through the daf-16/FOXO-sir-2.1/Sirtuin signalling network. We show that depletion of AMPK enhances neuronal impairment, and that activation by metformin induces neuroprotection, suggesting that this enzyme may be of therapeutic interest to fight the early phases of HD. We tested depletion and activation of this enzyme, in striatal cells from knock-in mice, a cell vulnerability model. Reducing AMPK, by siRNA, enhanced the susceptibility to cell death in mutant htt cells, and AMPK activation promotes striatal cell survival. Interestingly, activation of AMPK in striatal cells reduces the level of soluble mutant htt, suggesting that AMPK activation may promote protein clearance in these cells. Finally, we show that expression of gain-of-function form of AMPK in mice, expressing N-terminal expanded htt, reduce the volume of the lesion caused by neurodegeneration in the striatum.
Conclusion These results strongly suggest that AMPK activation protects from the early phases of mutant htt cytoxicity in several models of HD.
- AMPK
- C. elegans
- cell vulnerability model
- early phases of HD
- sirtuin
- FOXO