title: Pcaf modulates polyglutamine pathology in a Drosophila model of Huntington's disease.
abstract: Huntingtin peptides with elongated polyglutamine domains, the root causes of Huntington's disease, hinder histone acetylation, which leads to transcriptional dysregulation. However, the range of acetyltransferases interacting with mutant Huntingtin has not been systematically evaluated. We used genetic interaction tests in Drosophila to determine whether specific acetyltransferases belonging to distinct protein families influence polyglutamine pathology. We found that flies expressing a mutant form of the Huntingtin protein (Httex1pQ93) exhibit reduced viability, which is further decreased by partial loss of Pcaf or nejire, while the tested MYST family acetyltransferases did not affect pathology. Reduced levels of Pcaf also led to the increased degeneration of photoreceptor neurons in the retina. Overexpression of Pcaf, however, was not sufficient to ameliorate these phenotypes, and the level of soluble Pcaf is unchanged in Httex1pQ93-expressing flies. Thus, our results indicate that while Pcaf has a significant impact on Huntington's disease pathology, therapeutic strategies aimed at elevating its levels are likely to be ineffective in ameliorating Huntington's disease pathology; however, strategies that aim to increase the specific activity of Pcaf remain to be tested.
authors.affiliation: Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA. lbodai@yahoo.com
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bodai
authors.forename: Judit
authors.initials: J
authors.lastname: Pallos
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D015151:Immunoblotting; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D029721:Drosophila Proteins; D051548:Histone Acetyltransferases; D010455:Peptides; C097188:polyglutamine; C470557:GCN5 protein, Drosophila; D000099224:p300-CBP-Associated Factor