The stress response factor daf-16 /FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Scientific Reports Année : 2017

The stress response factor daf-16 /FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease

Francesca Farina
Emmanuel Lambert
  • Fonction : Auteur
François-Xavier Lejeune
Nathalie Roudier
  • Fonction : Auteur
Cosima Fonte
  • Fonction : Auteur
J. Alex Parker
  • Fonction : Auteur
Etienne-Emile Baulieu
  • Fonction : Auteur
Christian Neri

Résumé

Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington’s disease (HD), Parkinson’s disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown. Using drug screening in C. elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q), we found that 3ß-Methoxy-Pregnenolone (MAP4343), 17ß-oestradiol (17ßE2) and 12 flavonoids including isoquercitrin promote neuronal function in 128Q nematodes. MAP4343, 17ßE2 and isoquercitrin also promote stress resistance in mutant Htt striatal cells derived from knock-in HD mice. Interestingly, daf-16/FOXO is required for MAP4343, 17ßE2 and isoquercitrin to sustain neuronal function in 128Q nematodes. This similarly applies to the GSK3 inhibitor lithium chloride (LiCl) and, as previously described, to resveratrol and the AMPK activator metformin. Daf-16/FOXO and the targets engaged by these compounds define a sub-network enriched for stress-response and neuronally-active pathways. Collectively, these data highlights the dependence on a daf-16/FOXO-interaction network as a common feature of several compound families for prolonging neuronal function in HD.

Dates et versions

hal-01545500 , version 1 (22-06-2017)

Identifiants

Citer

Francesca Farina, Emmanuel Lambert, Lucie Commeau, François-Xavier Lejeune, Nathalie Roudier, et al.. The stress response factor daf-16 /FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease. Scientific Reports, 2017, 7 (1), pp.4014. ⟨10.1097/MCO.0000000000000382⟩. ⟨hal-01545500⟩
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