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Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway

Unité de Biologie Fonctionnelle et Adaptative (BFA), Université de Paris-CNRS, UMR8251 4 rue Marie Andrée Lagroua Weill Halle, CEDEX 13, 75205 Paris, France
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Author to whom correspondence should be addressed.
Current Adress: F. Hoffmann-La Roche Ltd., Product Development Global Operations, CNS and Rare Diseases, Basel Headquarter, Building: 663, 4070 Basel, Switzerland.
Academic Editor: Philippe Gasque
Int. J. Mol. Sci. 2021, 22(8), 3884; https://doi.org/10.3390/ijms22083884
Received: 29 January 2021 / Revised: 23 March 2021 / Accepted: 6 April 2021 / Published: 9 April 2021
Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although HTT is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD. View Full-Text
Keywords: Huntington’s disease; Drosophila; CBP; Foxo; Wnt signaling Huntington’s disease; Drosophila; CBP; Foxo; Wnt signaling
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MDPI and ACS Style

Martin, E.; Heidari, R.; Monnier, V.; Tricoire, H. Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway. Int. J. Mol. Sci. 2021, 22, 3884. https://doi.org/10.3390/ijms22083884

AMA Style

Martin E, Heidari R, Monnier V, Tricoire H. Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway. International Journal of Molecular Sciences. 2021; 22(8):3884. https://doi.org/10.3390/ijms22083884

Chicago/Turabian Style

Martin, Elodie, Raheleh Heidari, Véronique Monnier, and Hervé Tricoire. 2021. "Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway" International Journal of Molecular Sciences 22, no. 8: 3884. https://doi.org/10.3390/ijms22083884

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