Trends in Neurosciences
Volume 22, Issue 6, 1 June 1999, Pages 248-255
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Persepctives on Disease
Recent advances in understanding the pathogenesis of Huntington's disease

https://doi.org/10.1016/S0166-2236(99)01415-0Get rights and content

Abstract

Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder that is characterized by abnormal involuntary movements (chorea), intellectual impairment and selective neuronal loss. The expansion of a polymorphic trinucleotide repeat (the sequence CAG that codes for glutamine) to a length that exceeds 40 repeat units in exon 1 of the gene, HD, correlates with the onset and progression of the disease. The protein encoded by HD, huntingtin, is normally localized in the cytoplasm, whereas the mutant protein is also found in the nucleus, suggesting that its translocation to this site is important for the pathogenesis of HD. Although several proteins that interact with huntingtin have been identified in vitro, the significance of these interactions with the mutant protein in the pathogenesis of HD has yet to be determined. Recent progress in the development of cellular and animal models for the disease have provided invaluable insights and resources for studying the disease mechanisms underlying HD, and will be useful for screening and evaluating possible therapeutic strategies.

Section snippets

Genetics and neuropathology of HD

Huntington's disease is an autosomal, dominantly inherited disorder characterized phenotypically by chorea, involuntary movements, dystonia, intellectual impairment and emotional disturbances14, 15. The gene HD, which is mutated in HD sufferers, was mapped to chromosome 4p16.3 in 1983 (Ref. 16) and cloned a decade later2. The mutation is an expanded polyglutamine repeat, (CAG)n, within exon 1 of the gene. In the normal population, the number of CAG repeats ranges from 6–35 whereas in

Studies on huntingtin localization

Using immunohistochemical, immunofluorescence and subcellular-fractionation methods, several studies have demonstrated that both normal and mutant huntingtin are primarily localized in the cytoplasm18, 20, 32. While both forms are present in the cytoplasm, a smaller fraction of the mutant protein is also localized in the nucleus of some neuronal cells (see Table 1 for a summary)21, 33. Wood and co-workers34 characterized huntingtin localization and showed apparent variations in the subcellular

Huntingtin-interacting proteins

Several groups have independently identified proteins that interact with huntingtin (see Table 2 for a summary). Two novel proteins that interact with N-terminal fragments of huntingtin and contain expanded polyglutamine repeats were identified: Huntingtin-associated protein 1 (HAP1)36 and huntingtin-interacting protein 1 (HIP1)37. The predicted amino-acid sequence of the HIP1 fragment exhibits significant similarity to cytoskeletal proteins, which suggests that HIP1 and huntingtin, by virtue

Knockout models

To investigate the normal function of the HD gene, three groups generated a knockout mouse model independently. Targeted disruption of the murine homolog of the human HD gene (Hdh) was found to be lethal in homozygous embryos42, 43, 44, which do not proceed to organogenesis and die before embryonic-day 8.5. In one study, mice that are heterozygous (Hdh+/−) for the Hdh null mutation display increased motor activity and cognitive deficits, and significant neuronal loss in the subthalamic nucleus42

Neuronal inclusions

Early EM studies showed ultrastructural changes such as clumps or circumscribed masses of osmophilic granules in the nucleus in a post-mortem examination of the cerebral cortex and caudate nucleus of HD patients55, 56. More recently, Davies and co-workers52 have described similar structures in Hdh exon-1 transgenic mice46 and referred to them as neuronal intranuclear inclusions (NIIs). They also presented evidence indicating that these structures consist of polyglutamine aggregates and are

Cellular models for HD

In a series of experiments Martindale et al.61 observed the formation of large intracytoplasmic aggregates in vitro and in vivo. The HD expression construct that was truncated at nucleotide 1955, close to the putative caspase-3 cleavage site, formed perinuclear aggregates more readily than full-length huntingtin when transfected into monkey kidney cells and rat cortical neuronal cultures; moreover, the formation of polyglutamine aggregates appeared to increase susceptibility to cell death

CAG-repeat models in flies and worms

Recently, two groups have created CAG-repeat transgenic Drosophila models where the genes encoding the proteins that are mutated in HD (Ref. 68) or SCA3 (Ref. 69) patients were expressed either in photoreceptor neurons of the flies' compound eye68, 69 or in the entire nervous system69. In both studies, the expression of polyglutamine-expanded protein in the eye led to late-onset neuronal degeneration whose timing and severity increased with longer polyglutamine-repeat lengths. However, in the

Concluding remarks

Although our understanding of the biology of CAG repeats continues to grow, a number of issues remain to be resolved, such as the central and controversial issue of the true role of polyglutamine aggregation. Should therapeutic strategies focus on preventing aggregate formation, or does the formation of these inclusion bodies actually have a protective effect? What is it in the nuclear environment that renders the cell vulnerable to the gain-in-function effects of polyglutamine expression when

Acknowledgements

The authors thank members of their laboratory, particularly Vin Charles, Georg Auburger and Ping Yu for their critical reading of the menuscript and helpful suggestions.

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