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

Elodie Martin,Hervé Tricoire,Raheleh Heidari,Véronique Monnier

doi:10.3390/ijms22083884

Abstract

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.

Highlights

Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease characterized clinically by motor, cognitive, and psychiatric deficits
Investigating several putative targets of the CBP acetyltransferase, we found that this phenotypic improvement was lost in Foxo null animals, suggesting that dCBP repress Foxo in mutant huntingtin (mHTT) expressing glial cells and that dCBP depletion relieves this repression and contributes to HD mitigation
HD is a devastating neurodegenerative disorder and the causal dominant mutation in the huntingtin gene (HTT) gene was identified more than 20 years ago, there is still no efficient treatment

Summary

Introduction

Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease characterized clinically by motor, cognitive, and psychiatric deficits. It is a rare disease with overall prevalence of 2–6 persons per 100,000, depending on the geographic area [1]. HD is caused by a CAG repeat expansion in exon 1 of the gene encoding the large (3144 a.a.) huntingtin (HTT) protein. When the number of trinucleotide repeats exceeds 40 in the mutated HTT gene (mHTT), the disease is fully penetrant with an age of onset around 45 years, depending on the length of the repeat (reviewed in [2]). No clinical trial has demonstrated treatment efficacy to slow down the disease [6,7]

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Conclusion