Trends in Neurosciences
Volume 23, Issue 9, 1 September 2000, Pages 387-392
Journal home page for Trends in Neurosciences

Perspective
Transcriptional dysregulation in Huntington’s disease

https://doi.org/10.1016/S0166-2236(00)01609-XGet rights and content

Abstract

Although the gene responsible for Huntington’s disease was discovered in 1993, the pathogenic mechanisms by which mutant huntingtin causes neuronal dysfunction and death remain unclear. However, increasing evidence suggests that mutant huntingtin disrupts the normal transcriptional program of susceptible neurons. Thus, transcriptional dysregulation might be an important pathogenic mechanism in Huntington’s disease.

Section snippets

Huntingtin is a polyglutamine-containing protein

The mutation in the HD gene is an expansion of a CAG repeat, a trinucleotide motif that encodes a polyglutamine stretch within the mature protein4. Although huntingtin has no clear homology to any known protein, several other polyglutamine-containing proteins have been identified. Abnormal expansion of such proteins occurs in other neurodegenerative diseases9, 10, 11, 12. The CAG-repeat diseases share striking common features, including adult onset, progressive neurodegeneration, generational

Abnormal nuclear localization of mutant huntingtin

Normal huntingtin is localized in the cytoplasm32, 33, 34 but mutant huntingtin in addition to being found in the cytoplasm is also found localized in the nucleus. In transgenic mice expressing exon 1 of the mutated human HD gene, nuclear translocation of the mutant protein is associated with increased huntingtin immunoreactivity, first diffusely within the nucleus and then around the nuclear pores. Invagination of the nuclear membrane is also observed35. The processes governing nuclear

Abnormal protein interactions of mutant huntingtin

A consistent finding is that mutant huntingtin has altered protein–protein interactions compared with wild type huntingtin54, 55, 56, 57, 58, 59, 60, 61, 62, 63. Both increased and decreased binding interactions of mutant huntingtin have been described. Yeast two-hybrid studies have uncovered numerous huntingtin-interacting proteins, many of which have altered interactions depending on the length of the polyglutamine moiety59, 64. In addition, many of these interactors are novel proteins with

Neurotransmitter receptor levels are altered in HD

Neurotransmitter alterations have been described in early-stage human HD autopsy material; many of these changes have been confirmed in transgenic mouse models of HD (94, 95, 96, 97). In transgenic HD mice, neurotransmitter receptors are affected selectively; downregulation of specific receptors argues against a generalized problem with receptor production. This receptor downregulation occurs only in transgenic lines with abnormal CAG-repeat numbers97. Decreases in receptor binding are

Mutant huntingtin disrupts transcription of specific genes

There is no a priori reason to suggest that mutant huntingtin-induced transcriptional dysregulation is limited to neurotransmitter receptor genes. Several groups have now found evidence that huntingtin affects the expression of several genes. For example, in PC12 cells transfected with exon 1 of mutated huntingtin, differential display RT-PCR was used to reveal the presence of numerous altered transcripts102. Examples were found of mRNAs that had decreased as well as those that had increased,

Concluding remarks

In spite of the discovery of the huntingtin gene in 1993, the mechanisms by which mutant huntingtin exerts its toxic effects remain unknown. The anatomical distribution of the expression of huntingtin is insufficient to account for the pattern of neuropathological damage observed in HD. Clinical neurologic symptoms might have as their basis, altered neurotransmitter receptor levels and disrupted synaptic transmission. Transcriptional dysregulation is emerging as a probable pathogenic mechanism,

Acknowledgements

The author thanks Shawn Handran, Ruth Luthi-Carter, Leslie Thompson and Anne Young for their careful reading of this manuscript and helpful comments. The author’s research was supported by grants from the National Institutes of Health (NS 01916 and NS 38106), the Hereditary Disease Foundation, Huntington’s Disease Society of America and the Glendorn Foundation.

References (105)

  • J.M. Ordway

    Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse

    Cell

    (1997)
  • L. Mangiarini

    Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice

    Cell

    (1996)
  • J.G. Hodgson

    A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration

    Neuron

    (1999)
  • F. Saudou

    Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions

    Cell

    (1998)
  • M.F. Peters

    Nuclear targeting of mutant huntingtin increases toxicity

    Mol. Cell. Neurosci.

    (1999)
  • E. Scherzinger

    Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo

    Cell

    (1997)
  • Y.F. Liu

    SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes

    J. Biol. Chem.

    (1997)
  • J.F. Gusella et al.

    Huntingtin: a single bait hooks many species

    Curr. Opin. Neurobiol.

    (1998)
  • A. Sittler

    SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates

    Mol. Cell

    (1998)
  • P. Kahlem

    Transglutaminase action imitates Huntington’s disease: selective polymerization of Huntingtin containing expanded polyglutamine

    Mol. Cell

    (1998)
  • M.W. Becher

    Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length

    Neurobiol. Dis.

    (1998)
  • S.W. Davies

    Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation

    Cell

    (1997)
  • G.R. Jackson

    Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons

    Neuron

    (1998)
  • I. Sanchez

    Caspase-8 is required for cell death induced by expanded polyglutamine repeats

    Neuron

    (1999)
  • V.J. Palombella

    The ubiquitin–proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB

    Cell

    (1994)
  • T. Nakajima

    Stabilization of p53 by adenovirus E1A occurs through its amino-terminal region by modification of the ubiquitin–proteasome pathway

    J. Biol. Chem.

    (1998)
  • A. Ciechanover

    The ubiquitin–proteasome proteolytic pathway

    Cell

    (1994)
  • M. Hochstrasser

    Ubiquitin, proteasomes, and the regulation of intracellular protein degradation

    Curr. Opin. Cell Biol.

    (1995)
  • H.L. Pahl et al.

    Control of gene expression by proteolysis

    Curr. Opin. Cell Biol.

    (1996)
  • S.J. Augood

    Reduction in enkephalin and substance P messenger RNA in the striatum of early grade Huntington’s disease: a detailed cellular in situ hybridization study

    Neuroscience

    (1996)
  • P.H. Reddy

    Recent advances in understanding the pathogenesis of Huntington’s disease

    Trends Neurosci.

    (1999)
  • P.S. Harper

    Huntington’s Disease

    (1991)
  • J.P. Vonsattel et al.

    Huntington’s disease

    J. Neuropathol. Exp. Neurol.

    (1998)
  • A novel gene containing a trinucleotide repeat that is unstable in Huntington’s disease chromosomes

    Cell

    (1993)
  • A.T. Hoogeveen

    Characterization and localization of the Huntington disease gene product

    Hum. Mol. Genet.

    (1993)
  • G.B. Landwehrmeyer

    Huntington’s disease gene: Regional and cellular expression in brain of normal and affected individuals

    Ann. Neurol.

    (1995)
  • P.G. Bhide

    Expression of normal and mutant huntingtin in the developing brain

    J. Neurosci.

    (1996)
  • E. Sapp

    Huntingtin localization in brains of normal and Huntington’s disease patients

    Ann. Neurol.

    (1997)
  • H.L. Paulson et al.

    Trinucleotide repeats in neurogenetic disorders

    Annu. Rev. Neurosci.

    (1996)
  • J.F. Gusella

    The genetic defect causing Huntington’s disease: repeated in other contexts?

    Mol. Med.

    (1997)
  • R.S. Reddy et al.

    The complex pathology of trinucleotide repeats

    Curr. Opin. Cell Biol.

    (1997)
  • A.B. Young

    Huntington’s Disease and other trinucleotide repeat disorders

  • A. Servadio

    Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals

    Nat. Genet.

    (1995)
  • D. Tait

    Ataxin-3 is transported into the nucleus and associates with the nuclear matrix

    Hum. Mol. Genet.

    (1998)
  • A.R. LaSpada

    Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

    Nature

    (1991)
  • A.N. Mhatre

    Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy [erratum Nat. Genet. (1994) 2, 214]

    Nat. Genet.

    (1993)
  • N.L. Chamberlain

    The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

    Nucleic Acids Res.

    (1994)
  • P. Kazemi-Esfarjani

    Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies

    Hum. Mol. Genet.

    (1995)
  • H-P. Gerber

    Transcriptional activation modulated by homopolymeric glutamine and proline stretches

    Science

    (1994)
  • S. Karlin et al.

    Trinucleotide repeats and long homopeptides in genes and proteins associated with nervous system disease and development

    Proc. Natl. Acad. Sci. U.S.A.

    (1996)
  • Cited by (356)

    • Epigenetic mechanisms in Huntington’s disease

      2019, Chromatin Signaling and Neurological Disorders
    View all citing articles on Scopus
    View full text