Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a polyglutamine tract in the huntingtin protein. We have developed PC12 cell lines in which the expression of an N-terminal truncation of huntingtin (N63) with either wild type (23Q) or expanded polyglutamine (148Q) can be induced by the removal of doxycycline. Differentiated PC12 cells induced to express N63-148Q showed cellular toxicity reaching up to 50% at 6 days post-induction. Histone acetyltransferase (HAT) activity and global histone acetylation was significantly decreased in cells expressing truncated huntingtin with mutant but not normal huntingtin. These data suggest that altered chromatin modification via reduction in coactivator activity may cause neuronal transcriptional dysregulation and contribute to cellular toxicity.
Igarashi
Shuichi
S
Department of Neuroscience, Brain Research Institute, Niigata University, I Asahimachi, Niigata 951-8585, Japan.
Morita
Hokuto
H
Bennett
Kyla M
KM
Tanaka
Yuji
Y
Engelender
Simone
S
Peters
Matthew F
MF
Cooper
Jillian K
JK
Wood
Jonathan D
JD
Sawa
Akira
A
Ross
Christopher A
CA
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D004318:Doxycycline / Q000378:metabolism; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection / Q000379:methods
C086055:HTT protein, human; D006657:Histones; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C097188:polyglutamine; D020932:Nerve Growth Factor; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D004318:Doxycycline