Trends in Neurosciences
ReviewLoss of normal huntingtin function: new developments in Huntington's disease research
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’
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