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

Abstract 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...

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Autores principales:	Francesca Farina, Emmanuel Lambert, Lucie Commeau, François-Xavier Lejeune, Nathalie Roudier, Cosima Fonte, J. Alex Parker, Jacques Boddaert, Marc Verny, Etienne-Emile Baulieu, Christian Neri
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6708c811da8d48d8a864bd74cd34faa5
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spelling	oai:doaj.org-article:6708c811da8d48d8a864bd74cd34faa52021-12-02T12:30:35ZThe stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease10.1038/s41598-017-04256-w2045-2322https://doaj.org/article/6708c811da8d48d8a864bd74cd34faa52017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04256-whttps://doaj.org/toc/2045-2322Abstract 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.Francesca FarinaEmmanuel LambertLucie CommeauFrançois-Xavier LejeuneNathalie RoudierCosima FonteJ. Alex ParkerJacques BoddaertMarc VernyEtienne-Emile BaulieuChristian NeriNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Francesca Farina Emmanuel Lambert Lucie Commeau François-Xavier Lejeune Nathalie Roudier Cosima Fonte J. Alex Parker Jacques Boddaert Marc Verny Etienne-Emile Baulieu Christian Neri The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease
description	Abstract 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.
format	article
author	Francesca Farina Emmanuel Lambert Lucie Commeau François-Xavier Lejeune Nathalie Roudier Cosima Fonte J. Alex Parker Jacques Boddaert Marc Verny Etienne-Emile Baulieu Christian Neri
author_facet	Francesca Farina Emmanuel Lambert Lucie Commeau François-Xavier Lejeune Nathalie Roudier Cosima Fonte J. Alex Parker Jacques Boddaert Marc Verny Etienne-Emile Baulieu Christian Neri
author_sort	Francesca Farina
title	The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease
title_short	The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease
title_full	The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease
title_fullStr	The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease
title_full_unstemmed	The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease
title_sort	stress response factor daf-16/foxo is required for multiple compound families to prolong the function of neurons with huntington’s disease
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6708c811da8d48d8a864bd74cd34faa5
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The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease

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