Background Huntington's disease (HD) is a neurodegenerative pathology induced by cell toxicity caused by polyglutamine (polyQ) expansion in the N terminal end of huntingtin (htt). Using C elegans transgenics that express expanded polyQs in neurons, we identified a gene network that is centred onto FoxO and that protects neurons from expanded polyQs screen for genes that modulate the early phases of expanded polyQ neurotoxicity. Among these genes, we identified AMPK, a well known energy sensor involved in lifespan and health span extension in worms and mammals.
Aims AMPK is amenable to be regulated by different drugs. Some of these drugs, like metformin, are approved for human use, hence AMPK may be of therapeutic interest in HD. Therefore, we sought to characterise AMPK in the context of neuronal vulnerability caused by expanded htt in different models.
Methods First, we investigated the function of AMPK in C elegans and its potential interaction with well established neuroprotective genes by using mutants and drugs, such as metformin. We then validated our results in an in vitro model of HD: striatal cells from HdhQ111 knock-in mice, carrying the expanded (109Q) or wild-type (7Q) alleles of htt. Finally, we tested the potential of AMPK activation in mice, by overexpressing a gain of function allele of AMPK-γ, which activates AMPK function.
Results By doing epistatic analysis in worms, we show that AMPK is required for neuroprotection through the FOXO/daf-16 signalling pathway. The depletion of AMPK enhances neuronal impairment, and activation by metformin induces neuroprotection, suggesting that this enzyme may be of therapeutic interest in HD. Similar findings were obtained in striatal cells from HdhQ111. Finally, preliminary results suggest that activation of AMPK protects from the neuropathological effects of N terminal expanded htt in a lentivirius based model of HD in mice.
Conclusion These results strongly suggest that AMPK is of therapeutic interest in HD and warrant further investigation of AMPK activity in HD neurons.
- C elegans
- Huntington's disease
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