Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylation
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Acetyltransferases / metabolism
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Animals
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Blotting, Western
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Cell Death
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Doxycycline / metabolism
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Histone Acetyltransferases
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Histones / metabolism
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Humans
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Huntingtin Protein
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Huntington Disease / chemically induced
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Huntington Disease / genetics
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Huntington Disease / metabolism*
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Nerve Growth Factor / pharmacology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nerve Tissue Proteins / pharmacology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nuclear Proteins / pharmacology
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PC12 Cells / drug effects
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PC12 Cells / metabolism*
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Peptide Fragments
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Peptides / chemistry
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Peptides / metabolism*
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Rats
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae Proteins / metabolism
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Time Factors
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Transcription, Genetic / physiology
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Transfection / methods
Substances
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HTT protein, human
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Histones
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Htt protein, rat
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Huntingtin Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptide Fragments
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Peptides
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Recombinant Proteins
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Saccharomyces cerevisiae Proteins
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polyglutamine
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Nerve Growth Factor
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Acetyltransferases
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Histone Acetyltransferases
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Doxycycline