Context-dependent dysregulation of transcription by mutant huntingtin.
Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments.
Cornett
Jonathan
J
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Smith
Lauren
L
Friedman
Meyer
M
Shin
Ji-Yeon
JY
Li
Xiao-Jiang
XJ
Li
Shi-Hua
SH
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic
D050956:HSP40 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor