Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila

  title={Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila},
  author={Joan S. Steffan and L{\'a}szl{\'o} Bodai and Judit Pallos and Marnix Poelman and Alexander McCampbell and Barbara L. Apostol and A Kazantsev and Emily Schmidt and Ya-zhen Zhu and Marilee Greenwald and Riki Kurokawa and David E. Housman and George R. Jackson and J. Lawrence Marsh and Leslie M. Thompson},
Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly… 
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.
Histone deacetylase activity is retained in primary neurons expressing mutant huntingtin protein
Perturbation of histone acetyl‐transferase (HAT) activity is implicated in the pathology of polyglutamine diseases, and suppression of the counteracting histone deacetylase (HDAC) proteins has been
Disassociation of Histone Deacetylase-3 from Normal Huntingtin Underlies Mutant Huntingtin Neurotoxicity
It is shown that Htt is a neuroprotective protein in both HD-related and unrelated model systems and identifies HDAC3 as an essential player in mutant Htt-induced neurodegeneration.
Differential Contributions of Caenorhabditis elegans Histone Deacetylases to Huntingtin Polyglutamine Toxicity
It is suggested that polyglutamine expansions perturb transcription of CREB/CBP targets and that specific targeting of HDACs will be useful in reducing associated neurodegeneration.
Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein.
It is demonstrated that polyglutamine-induced neurodegeneration is accompanied by a defect in histone acetylation and a substantial alteration in the transcription profile, and that transcriptional dysregulation is an important part of the pathogenesis of polyglutanism.
Histone deacetylase inhibitors as therapeutics for polyglutamine disorders
The potential therapeutic pathways through which histone deacetylase inhibitors might act to correct the aberrant transcription observed in Huntington's disease and other polyglutamine repeat diseases are discussed.
Altered Histone Monoubiquitylation Mediated by Mutant Huntingtin Induces Transcriptional Dysregulation
This is the first report to demonstrate hPRC1L as a huntingtin-interacting histone modifying complex and a crucial role for histone monoubiquitylation in mammalian brain gene expression, which broadens the understanding of histone code.
Selective inhibition of histone deacetylase 1 and 3 improves motor phenotype and alleviates transcriptional dysregulation in Huntington’s disease mice
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an
Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila.
The data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.


CREB-binding protein sequestration by expanded polyglutamine.
Evidence is presented that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA.
The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.
The possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD is raised.
Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity
It is found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain, suggesting polyglUTamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutsamine disorders.
Identification of genes that modify ataxin-1-induced neurodegeneration
It is shown that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein, and may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila.
This animal model provides a simple and effective means of screening for therapeutics that relieves the polyQ-induced lethality, independent of any particular disease gene, by quantifying the degree of lethality in several transgenic lines.
Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold.
  • H. Paulson
  • Biology
    American journal of human genetics
  • 1999
This review examines the fate of mutant protein in neurons and the potential role of posttranslational events in pathogenesis, with particular focus on the polygln diseases.
Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells.
The CREB-binding protein (CBP), containing a homopolymeric stretch of 19 glutamines, was likewise found to coaggregate in a polyglutamine-dependent manner, suggesting that pathology in polyglUTamine disease may result from cellular depletion of normal proteins containing poly glutamine.
Protein Aggregation and Pathogenesis of Huntingtons Disease: Mechanisms and Correlations
During the last three years, considerable effort has been invested in the development of in vitro and in vivo model systems to study the mechanisms of protein aggregation in glutamine-repeat disorders and its potential effects on disease progression and neurodegeneration.
Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells.
The working hypothesis is that inhibition of HDAC activity leads to the modulation of expression of a specific set of genes that, in turn, result in growth arrest, differentiation, and/or apoptotic cell death.
Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology.
It is reported that the formation of amyloid-like huntingtin aggregates in vitro not only depends on poly(Q) repeat length but also critically depends on protein concentration and time, and the in vitro aggregation of huntingtin can be seeded by preformed fibrils.