Mechanisms of Disease: histone modifications in Huntington's disease

  title={Mechanisms of Disease: histone modifications in Huntington's disease},
  author={Ghazaleh Sadri-Vakili and Jang-Ho Cha},
  journal={Nature Clinical Practice Neurology},
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine repeat expansion within the huntingtin protein. HD is characterized by problems with movement, cognition and behavioral functioning, and there is currently no effective treatment. Although multiple pathologic mechanisms have been proposed, the exact mechanism by which mutant huntingtin causes neuronal dysfunction is not known. Recent studies demonstrating altered messenger RNA expression… 
Epigenetic Mechanisms of Neurodegeneration in Huntington’s Disease
How DNA methylation, post-translational modifications of histone, and noncoding RNA function are affected and involved in HD pathogenesis and the therapeutic effects of hist one deacetylase inhibitors and DNA binding drugs on epigenetic modifications and neuropathological sequelae in HD are discussed.
Inconsistencies in histone acetylation patterns among different HD model systems and HD post-mortem brains
Genome-Wide Histone Acetylation Is Altered in a Transgenic Mouse Model of Huntington's Disease
It is demonstrated that histone H3 acetylation at lysine residues 9 and 14 and active gene expression are intimately tied in the rodent brain, and that this fundamental relationship remains unchanged in an HD mouse model despite genome-wide decreases in hist one H3acetylation.
Nucleolar dysfunction in Huntington's disease.
Chromosomal profiles of gene expression in Huntington's disease.
Results show that transcription is indeed deregulated in large genomic regions in coordinated fashion, that transcription in these regions is associated with disease progression and that altered chromosomal clusters in the two tissues are remarkably similar.
Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease
This review addresses the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs).
Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models.
It is demonstrated that despite no change in overall acetylated histone levels, histone H3 is hypo-acetylated at promoters of downregulated genes in R6/2 mice, ST14a and STHdh cells, as demonstrated by in vivo chromatin immunoprecipitation.
Modulation of nucleosome dynamics in Huntington's disease.
Improved nucleosomal dynamics were concurrent with a significant improvement in the behavioral and neuropathological phenotype observed in HD mice, showing the ability of anthracycline compounds to rebalance epigenetic histone modification and may provide the rationale for the design of human clinical trials in HD patients.
Transcriptional signatures in Huntington's disease
  • J. Cha
  • Biology
    Progress in Neurobiology
  • 2007
Molecular mechanisms and potential therapeutical targets in Huntington's disease.
The data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution are reviewed and data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive are summarized.


Transcriptional dysregulation in Huntington's disease
Biological pathway analysis within the Gene Ontology framework showed that acute treatment with novel small-molecule SIRT2 inhibitors caused the downregulation of genes associated with sterol and lipid metabolism in both wild-type and polyQ htt expressing cells.
Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
It is shown that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF).
Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice
Findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.
Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease
Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity.
Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation
The data suggest that altered chromatin modification via reduction in coactivator activity may cause neuronal transcriptional dysregulation and contribute to cellular toxicity.
Neuroprotective Effects of Phenylbutyrate in the N171-82Q Transgenic Mouse Model of Huntington's Disease*
Results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and therefore represents a very promising therapeutic approach for HD.
Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease
  • E. Hockly, V. Richon, G. Bates
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
Preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, show that SAHA crosses the blood–brain barrier and increases histone acetylation in the brain, clearly validating the pursuit of this class of compounds as HD therapeutics.
Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease
Evidence of caspase-1 activation in the brains of mice and humans with Huntington's disease is demonstrated and it is demonstrated that intracerebroventricular administration of a casp enzyme inhibitor delays disease progression and mortality in the mouse model of Huntington’s disease.
Histone deacetylase inhibitors reduce polyglutamine toxicity
It is suggested that nuclear accumulation of polyglutamine can lead to altered protein acetylation in neurons and indicate a novel therapeutic strategy for polyglUTamine disease.