Dynamic regulation of molecular chaperone gene expression in polyglutamine disease.
Expanded polyglutamine disease proteins cause adult-onset progressive neurodegeneration. Constitutive overexpression of the Hsp70 molecular chaperone is capable of suppressing polyglutamine neurodegeneration. We showed that endogenous Hsp70 expression was induced, at both transcriptional and translational levels, in Drosophila models of polyglutamine disease. Soon after the endogenous Hsp70 induction reached a maximum level at larval stage, its expression declined progressively with age. We further showed that cellular heat shock response remained intact in aged flies, indicating the decline of Hsp70 levels observed in polyglutamine-expressing flies is not due to normal ageing. In contrast to the well-documented polyglutamine suppression caused by constitutive Hsp70 overexpression, no suppression of degeneration was observed when inducible copies of hsp70 transgenes were instead coexpressed. This supports a transcriptional dysregulation of endogenous hsp70 gene induction in polyglutamine flies. Altogether, we propose that transcriptional malfunctioning of molecular chaperone gene expression contributes to the late-onset and progressive nature of polyglutamine toxicity.
Huen
N Y Macy
NY
Laboratory of Drosophila Research, Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
Chan
H Y Edwin
HY
D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D020271:Heredodegenerative Disorders, Nervous System / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D015533:Transcriptional Activation
D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D010455:Peptides; C097188:polyglutamine