Trends in Neurosciences
Volume 24, Issue 3, 1 March 2001, Pages 182-188
Journal home page for Trends in Neurosciences

Review
Loss of normal huntingtin function: new developments in Huntington's disease research

https://doi.org/10.1016/S0166-2236(00)01721-5Get rights and content

Abstract

Huntington's disease is characterized by a loss of brain striatal neurons that occurs as a consequence of an expansion of a CAG repeat in the huntingtin protein. The resulting extended polyglutamine stretch confers a deleterious gain-of-function to the protein. Analysis of the mutant protein has attracted most of the research activity in the field, however re-examination of earlier data and new results on the beneficial functions of normal huntingtin indicate that loss of the normal protein function might actually equally contribute to the pathology. Thus, complete elucidation of the physiological role(s) of huntingtin and its mode of action are essential and could lead to new therapeutic approaches.

Section snippets

Molecular pathology of Huntington's disease

The presence of intranuclear and cytoplasmic aggregates of mutant huntingtin in HD brains and in animal models of the disease has been widely reported 17. Aggregates have also been found in dystrophic neurites and in the neuropil of postmortem HD brains 18, 19, 20. The role of these aggregates in HD pathogenesis remains controversial (reviewed in 21, 22), but recent evidence obtained in mice that have either a mutant full length human huntingtin or a pathological CAG insertion into the mouse HD

Analyses of the gain-of-function hypothesis in HD: evidence from studies in patients

Most of the compelling evidence against a simple loss of molecular function in HD is derived from the genetic studies and from the fact that deletion of one huntingtin allele (in the Wolf–Hirschhorn syndrome) does not result in HD 33. Thus, one mutant allele is necessary for disease manifestation, and heterozygous HD patients exhibit the full spectrum of phenotypes. However, neither of these pieces of evidence excludes a contribution to the disease from the loss of normal huntingtin.

Other

Evidence from huntingtin knockout mice

The fact that the embryos of huntingtin homozygous knockout mice die by day 7.5 48, 49, 50 had always been considered as proof of the gain-of-function hypothesis in HD. Two heterozygous knockout mice, with only half the normal level of huntingtin, pass the development stage and reach adulthood, in which a normal phenotype was observed 48, 50. In another knockout model (in which the mice produced a truncated N-terminal fragment of the protein), the heterozygotes showed increased motor activity,

In search of the function of normal huntingtin

In spite of early recognition that normal huntingtin function is required for embryonic development, evidence of its function in brain cells over the whole lifetime was lacking. Interestingly, although the sequence of the gene is highly conserved phylogenetically, there are striking differences in the number of triplet repeats carried by the normal gene in different species. Whereas the human huntingtin gene carries a normal polymorphic CAG stretch ranging from 9 to 35 repeats 53, the rat and

Direct evidence of a function for huntingtin in cell survival and neuronal stability

Studies by Rigamonti et al. 10 have provided the first direct evidence for a role of huntingtin on the survival of CNS cells 10. Striatal cells that were engineered to express wild-type huntingtin were indeed resistant to the lethal effect of stresses such as serum deprivation (Fig. 2a), exposure to 3-nitropropionic acid (Fig. 3) (a mitochondrial toxin that, when injected systemically into animals, gives a similar pattern of neurodegeneration compared with that observed in HD, reviewed in 83 or

Selective vulnerability

An issue remaining unexplained is the specific vulnerability of striatal neurones in HD. Following the cloning of huntingtin it was suggested that the specificity of cell loss was as a result of a pathogenic interaction of mutant huntingtin with striatum-specific molecules. However, an extensive search for such molecules has identified brain-specific, but not striatum-specific, proteins with which mutant huntingtin preferentially interacts. Another possible explanation for the selective

Concluding remarks

This review has re-examined the evidence that a loss of huntingtin function might contribute to HD. In practical terms, identifying all possible routes through which a disease is manifested broadens our therapeutic perspectives. In HD, whereas one approach aims at blocking the aberrant activity that is caused by the lengthened CAG repeat, an additional strategy might be to restore normal huntingtin function. With current technologies this might be achieved either via gene therapy approaches or

Acknowledgments

The authors wish to thank two anonymous reviewers for their enthusiastic comments and encouragement; S. Zeitlin for sharing unpublished results; Nat. Genetics and S. Zeitlin for permission to reprint part of his work. The work of the authors described in this paper was funded by the Huntington's Disease Society of America (H.D.S.A.), the Hereditary Disease Foundation (H.D.F.), Telethon (Italy, #E840), C.N.R. (Italy, #98.01050.CT04) to EC. EC is a member of the ‘Coalition for the Cure’

References (86)

  • C.L Wellington

    Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract

    J. Biol. Chem.

    (1998)
  • C.L Wellington

    Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells

    J. Biol. Chem.

    (2000)
  • J.H Cha

    Transcriptional dysregulation in Huntington's disease (2000)

    Trends Neurosci.

    (2000)
  • J Nasir

    Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioural and morphological changes in heterozygotes

    Cell

    (1995)
  • 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)
  • Y.F Liu

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

    J. Biol. Chem.

    (1997)
  • M.A Kalchman

    Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme

    J. Biol. Chem.

    (1996)
  • Y.F Liu

    Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin

    J. Biol. Chem.

    (2000)
  • A Sittler

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

    Mol. Cell.

    (1998)
  • J.F Gusella et al.

    Huntingtin: a single bait hooks many species

    Curr. Opin. Neurobiol.

    (1998)
  • M DiFiglia

    Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons

    Neuron

    (1995)
  • J Velier

    Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways

    Exp. Neurol.

    (1998)
  • M Kim

    Forskolin and dopamine D1 receptor activation increase huntingtin's association with endosomes in immortalized neuronal cells of striatal origin

    Neuroscience

    (1999)
  • I.R Vetter

    Structural view of the Ran-Importin beta interaction at 2.3 A resolution

    Cell

    (1999)
  • M.F Beal

    Energetics in the pathogenesis of neurodegenerative diseases

    Trends Neurosci.

    (2000)
  • Huntington's Disease Collaborative Research Group. (1993) A novel gene containing a trinucleotide repeat that is...
  • G.J.P Vonsattel et al.

    Huntington Disease

    J. Neuropath. Exp. Neur.

    (1998)
  • Y Trottier

    Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form

    Nat. Genet.

    (1995)
  • H Ikeda

    Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo

    Nat. Genet.

    (1996)
  • D Rigamonti

    Wild-type huntingtin protects from apoptosis upstream of caspase-3

    J. Neurosci.

    (2000)
  • I Dragatsis

    Inactivation of the mouse huntington's disease gene in the brain and testis results in progressive neurodegeneration and sterility

    Nat. Genet.

    (2000)
  • C.C Huang

    Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins

    Somat. Cell Molec. Gen.

    (1998)
  • V.C Wheeler

    Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice

    Hum. Mol. Genet.

    (2000)
  • A Kazantsev

    Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells

    Proc. Natl. Acad. Sci. USA

    (1999)
  • V.O Ona

    Inhibition of caspase-1 slows disease progression in a mouse model of Huntingtons disease

    Nature

    (1999)
  • M Chen

    Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease

    Nat. Med.

    (2000)
  • M DiFiglia

    Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain

    Science

    (1997)
  • C.A Gutekunst

    Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology

    J. Neurosci.

    (1999)
  • S.H Li

    Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity

    Nat. Genet.

    (2000)
  • Y.P Goldberg

    Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract

    Nat. Genet.

    (1996)
  • J.K Cooper

    Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture

    Hum. Mol. Genet.

    (1998)
  • J.M Boutell

    Aberrant interactions of transcriptional repressor proteins with the Huntington's disease gene product, huntingtin

    Hum. Mol. Genet.

    (1999)
  • A Wyttenbach

    Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease

    Proc. Natl. Acad. Sci. USA

    (2000)
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