Trends in Neurosciences
PerspectiveTranscriptional dysregulation 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)
The functional anatomy of basal ganglia disorders
Trends Neurosci.
(1989)- et al.
Trinucleotide repeats in neurologic disease: An hypothesis concerning the pathogenesis of Huntington’s Disease, Kennedy’s Disease, and Spinocerebellar ataxia Type 1
Life Sci.
(1994) Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases?
Neuron
(1997)Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions?
Lancet
(1998)Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice
Cell
(1998)Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity
J. Biol. Chem.
(1999)Heterogeneous intracellular localization and expression of ataxin-3
Neurobiol. Dis.
(1998)Transcriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy
J. Neurol. Sci.
(1996)Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons
Neuron
(1995)Widespread expression of Huntington’s disease gene (IT15) protein product
Neuron
(1995)
Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse
Cell
Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice
Cell
A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration
Neuron
Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions
Cell
Nuclear targeting of mutant huntingtin increases toxicity
Mol. Cell. Neurosci.
Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo
Cell
SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes
J. Biol. Chem.
Huntingtin: a single bait hooks many species
Curr. Opin. Neurobiol.
SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates
Mol. Cell
Transglutaminase action imitates Huntington’s disease: selective polymerization of Huntingtin containing expanded polyglutamine
Mol. Cell
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.
Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation
Cell
Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons
Neuron
Caspase-8 is required for cell death induced by expanded polyglutamine repeats
Neuron
The ubiquitin–proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB
Cell
Stabilization of p53 by adenovirus E1A occurs through its amino-terminal region by modification of the ubiquitin–proteasome pathway
J. Biol. Chem.
The ubiquitin–proteasome proteolytic pathway
Cell
Ubiquitin, proteasomes, and the regulation of intracellular protein degradation
Curr. Opin. Cell Biol.
Control of gene expression by proteolysis
Curr. Opin. Cell Biol.
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
Recent advances in understanding the pathogenesis of Huntington’s disease
Trends Neurosci.
Huntington’s Disease
Huntington’s disease
J. Neuropathol. Exp. Neurol.
A novel gene containing a trinucleotide repeat that is unstable in Huntington’s disease chromosomes
Cell
Characterization and localization of the Huntington disease gene product
Hum. Mol. Genet.
Huntington’s disease gene: Regional and cellular expression in brain of normal and affected individuals
Ann. Neurol.
Expression of normal and mutant huntingtin in the developing brain
J. Neurosci.
Huntingtin localization in brains of normal and Huntington’s disease patients
Ann. Neurol.
Trinucleotide repeats in neurogenetic disorders
Annu. Rev. Neurosci.
The genetic defect causing Huntington’s disease: repeated in other contexts?
Mol. Med.
The complex pathology of trinucleotide repeats
Curr. Opin. Cell Biol.
Huntington’s Disease and other trinucleotide repeat disorders
Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals
Nat. Genet.
Ataxin-3 is transported into the nucleus and associates with the nuclear matrix
Hum. Mol. Genet.
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy
Nature
Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy [erratum Nat. Genet. (1994) 2, 214]
Nat. Genet.
The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function
Nucleic Acids Res.
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.
Transcriptional activation modulated by homopolymeric glutamine and proline stretches
Science
Trinucleotide repeats and long homopeptides in genes and proteins associated with nervous system disease and development
Proc. Natl. Acad. Sci. U.S.A.
Cited by (356)
Haplotype-specific insertion-deletion variations for allele-specific targeting in Huntington's disease
2022, Molecular Therapy Methods and Clinical DevelopmentEpigenetic mechanisms in Huntington’s disease
2019, Chromatin Signaling and Neurological DisordersRNA Aptamers Rescue Mitochondrial Dysfunction in a Yeast Model of Huntington's Disease
2018, Molecular Therapy Nucleic AcidsThe role of Twist1 in mutant huntingtin–induced transcriptional alterations and neurotoxicity
2018, Journal of Biological Chemistry