Abstract
Huntington’s disease (HD) research is aimed at understanding the root cause of the disorder, for the thrill of uncovering new biology, and for the serious purpose of finding effective therapeutic agents. Molecular genetics has revealed the disease trigger, an inherited unstable CAG expansion in a novel 4p16.3 gene (HD), that lengthens a polyglutamine segment in huntingtin. Now studies with HD patients and model systems that are genetic HD replicas are homing in on the trigger mechanism and the first formative steps that cast HD as a distinct clinical entity. At the same time, assays at the biochemical, cellular, and whole organism levels are starting to yield potential disease modifying genes and candidate drugs. These can be prioritized by testing in a panel of genetic and phenotypic HD mouse models to yield analytical tools for dissecting the early and late stages of the disease process and to maximize the chance of success in trials with HD patients.
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Albin R. L. and Greenamyre J. T. (1992) Alternative excitotoxic hypotheses. Neurology 42, 733–738.
Andrade M. A., Petosa C., O’Donoghue S. I., Muller C. W., and Bork P. (2001) Comparison of ARM and HEAT protein repeats. J. Mol. Biol. 309, 1–18.
Andreassen O. A., Ferrante R. J., Dedeoglu A., and Beal M. F. (2001) Lipoic acid improves survival in transgenic mouse models of Huntington’s disease. Neuroreport 12, 3371–3373.
Berke S. J. and Paulson H. L. (2003) Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration. Curr. Opin. Genet. Dev. 13, 253–261.
Chan E. Y., Luthi-Carter R., Strand A., et al. (2002) Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington’s disease. Hum. Mol. Genet. 11, 1939–1951.
Chen M., Ona V. O., Li M., et al. (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat. Med. 6, 797–801.
Chen S., Ferrone F. A., and Wetzel R. (2002) Huntington’s disease age-of-onset linked to polyglutamine aggregation nucleation. Proc. Natl. Acad. Sci. USA 99, 11884–11889.
Davies S. W., Turmaine M., Cozens B. A., et al. (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548.
Dedeoglu A., Kubilus J. K., Yang L., et al. (2003) Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J. Neurochem. 85, 1359–1367.
De Rooij K. E., Dorsman J. C., Smoor M. A., Den Dunnen J. T., and Van Ommen G. J. (1996) Subcellular localization of the Huntington’s disease gene product in cell lines by immunofluorescence and biochemical subcellular fractionation. Hum. Mol. Genet. 5, 1093–1099.
Dragatsis I., Levine M. S., and Zeitlin S. (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 26, 300–306.
Duan W., Guo Z., Jiang H., et al. (2003) Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc. Natl. Acad. Sci. USA 100, 2911–2916.
Duyao M. P., Auerbach A. B., Ryan A., et al. (1995) Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science 269, 407–410.
Ferrante R. J., Andreassen O. A., Dedeoglu A., et al. (2002) Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J. Neurosci. 22, 1592–1599.
Fossale E., Wheeler V. C., Vrbanac V., et al. (2002) Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice. Hum. Mol. Genet. 11, 2233–2241.
Friedlander R. M. (2003) Apoptosis and caspases in neurodegenerative diseases. N. Engl. J. Med. 348, 1365–1375.
Gafni J. and Ellerby L. M. (2002) Calpain activation in Huntington’s disease. J. Neurosci. 22, 4842–4849.
Gines S., Seong I. S., Fossale E., et al. (2003) Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington’s disease knock-in mice. Hum. Mol. Genet. 12, 497–508.
Gusella J. and MacDonald M. (2002) No post-genetics era in human disease research. Nat. Rev. Genet. 3, 72–79.
Gusella J. F. and MacDonald M. E. (2000) Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat. Rev. Neurosci. 1, 109–115.
HDCRG (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983.
Heiser V., Scherzinger E., Boeddrich A., et al. (2000) Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington’s disease therapy. Proc. Natl. Acad. Sci. USA 97, 6739–6744.
Hilditch-Maguire P., Trettel F., Passani L. A., et al. (2000) Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum. Mol. Genet. 9, 2789–2797.
Hockly E., Cordery P. M., Woodman B., et al. (2002) Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann. Neurol. 51, 235–242.
Hockly E., Richon V. M., Woodman B., et al. (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc. Natl. Acad. Sci. USA 100, 2041–2046.
Huang C. C., Faber P. W., Persichetti F., et al. (1998) Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat. Cell Mol. Genet. 24, 217–233.
Jones L. (2000) Huntington-interacting proteins and their relevance to Huntington’s disease etiology. NeuroSci. News 3, 55–63.
Karpuj M. V., Becher M. W., and Steinman L. (2002) Evidence for a role for transglutaminase in Huntington’s disease and the potential therapeutic implications. Neurochem. Int. 40, 31–36.
Keene C. D., Rodrigues C. M., Eich T., et al. (2002) Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. Proc. Natl. Acad. Sci. USA 99, 10671–10676.
Kegel K. B., Meloni A. R., Yi Y., et al. (2002) Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription. J. Biol. Chem. 277, 7466–7476.
Kehoe P., Krawczak M., Harper P. S., Owen M. J., and Jones A. L. (1999) Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J. Med. Genet. 36, 108–111.
Kennedy L. and Shelbourne P. F. (2000) Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington’s disease? Hum. Mol. Genet. 9, 2539–2544.
Laforet G. A., Sapp E., Chase K., et al. (2001) Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. J. Neurosci. 21, 9112–9123.
Leavitt B. R., Guttman J. A., Hodgson J. G., et al. (2001) Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. Am. J. Hum. Genet. 68, 313–324.
Levine M. S., Klapstein G. J., Koppel A., et al. (1999) Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J. Neurosci. Res. 58, 515–532.
Li. J-L., Hayden M., Almqvist E. W., et al. (2003) A genome scan for modifiers of age at onset in Huntington’s disease: the HD MAPS study. Am. J. Hum. Genet. 73, 682–687.
Li H., Li S. H., Yu Z. X., Shelbourne P., and Li X. J. (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington’s disease mice. J. Neurosci. 21, 8473–8481.
Li H., Li S. H., Johnston H., Shelbourne P. F., and Li X. J. (2000) Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat. Genet. 25, 385–389.
Lin C. H., Tallaksen-Greene S., Chien W. M., et al. (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum. Mol. Genet. 10, 137–144.
Luthi-Carter R., Hanson S. A., Strand A. D., et al. (2002) Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum. Mol. Genet. 11, 1911–1926.
MacDonald M. E., Vonsattel J. P., Shrinidhi J., et al. (1999) Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease. Neurology 53, 1330–1332.
Mangiarini L., Sathasivam K., Seller M., et al. (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506.
Martin J. B. and Gusella J. F. (1986) Huntington’s disease. Pathogenesis and management. N. Engl. J. Med. 315, 1267–1276.
Menalled L., Zanjani H., MacKenzie L., et al. (2000) Decrease in striatal enkephalin mRNA in mouse models of Huntington’s disease. Exp. Neurol. 162, 328–342.
Menalled L. B., Sison J. D., Wu Y., et al. (2002) Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington’s disease knock-in mice. J. Neurosci. 22, 8266–8276.
Miyoshi K., Tsujii R., Yoshida H., et al. (2002) Normal assembly of 60 S ribosomal subunits is required for the signaling in response to a secretory defect in Saccharomyces cerevisiae. J. Biol. Chem. 277, 18334–18339.
Muchowski P. J. (2002) Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones? Neuron 35, 9–12.
Myers R. H., Leavitt J., Farrer L. A., et al. (1989) Homozygote for Huntington disease. Am. J. Hum. Genet. 45, 615–618.
Naze P., Vuillaume I., Destee A., Pasquier F., and Sablonniere B. (2002) Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington’s disease. Neurosci. Lett. 328, 1–4.
Ona V. O., Li M., Vonsattel J. P., et al. (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 399, 263–267.
Panas M., Avramopoulos D., Karadima G., Petersen M. B., and Vassilopoulos D. (1999) Apolipoprotein E and presenilin-1 genotypes in Huntington’s disease. J. Neurol. 246, 574–577.
Panov A. V., Burke J. R., Strittmatter W. J., and Greenamyre J. T. (2003) In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington’s disease. Arch. Biochem. Biophys. 410, 1–6.
Panov A. V., Gutekunst C. A., Leavitt B. R., et al. (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat. Neurosci. 5, 731–736.
Penney J. B., Jr., Vonsattel J. P., MacDonald M. E., Gusella J. F., and Myers R. H. (1997) CAG repeat number governs the development rate of pathology in Huntington’s disease. Ann. Neurol. 41, 689–692.
Persichetti F., Carlee L., Faber P. W., et al. (1996) Differential expression of normal and mutant Huntington’s disease gene alleles. Neurobiol. Dis. 3, 183–190.
Ross C. A. (2002) Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron 35, 819–822.
Rubinsztein D. C., Leggo J., Chiano M., et al. (1997) Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc. Natl. Acad. Sci. USA 94, 3872–3876.
Sanchez I., Mahlke C., and Yuan J. (2003) Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379.
Sawa A., Wiegand G. W., Cooper J., et al. (1999) Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat. Med. 5, 1194–1198.
Scherzinger E., Sittler A., Schweiger K., et al. (1999) Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc. Natl. Acad. Sci. USA 96, 4604–4609
Scherzinger E., Lurz R., Turmaine M., et al. (1997) Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90, 549–558.
Schiefer J., Landwehrmeyer G. B., Luesse H. G., et al. (2002) Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse models of Huntington’s disease. Mov. Disord. 17, 748–757.
Schilling G., Coonfield M. L., Ross C. A., and Borchelt D. R. (2001) Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model. Neurosci. Lett. 315, 149–153
Schilling G., Becher M. W., Sharp A. H., et al. (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 8, 397–407.
Shelbourne P. F., Killeen N., Hevner R. F., et al. (1999) A Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum. Mol. Genet. 8, 763–774.
Slow E. J., Van Raamsdonk J., Rogers D., et al. (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 12, 1555–1567.
Sugars K. L. and Rubinsztein D. C. (2003) Transcriptional abnormalities in Huntington disease. Trends Genet. 19, 233–238.
Takano H. and Gusella J. F. (2002) The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci. 3, 15.
The Huntington Study Group (2001) A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurol. 57, 397–404.
Trettel F., Rigamonti D., Hilditch-Maguire P., et al. (2000) Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum. Mol. Genet. 9, 2799–2809.
Trottier Y., Lutz Y., Stevanin G., et al. (1995) Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 378, 403–406.
Tsuno A., Miyoshi K., Tsujii R., Miyakawa T., and Mizuta K. (2000) RRS1, a conserved essential gene, encodes a novel regulatory protein required for ribosome biogenesis in Saccharomyces cerevisiae. Mol. Cell Biol. 20, 2066–2074.
Velier J., Kim M., Schwarz C., et al. (1998) Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways. Exp. Neurol. 152, 34–40.
Vonsattel J. P. and DiFiglia M. (1998) Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369–384.
Wheeler V. C., Lebel L. A., Vrbanac V., et al. (2003) Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Hum. Mol. Genet. 12, 273–281.
Wheeler V. C., Gutekunst C. A., Vrbanac V., et al. (2002) Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum. Mol. Genet. 11, 633–640
Wheeler V. C., White J. K., Gutekunst C. A., et al. (2000) Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knockin mice. Hum. Mol. Genet. 9, 503–513.
Wheeler V. C., Auerbach W., White J. K., et al. (1999) Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse. Hum. Mol. Genet. 8, 115–122
White J. K., Auerbach W., Duyao M. P., et al. (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat. Genet. 17, 404–410.
Xia J., Lee D. H., Taylor J., Vandelft M., and Truant R. (2003) Huntingtin contains a highly conserved nuclear export signal. Hum. Mol. Genet. 12, 1393–1403.
Zeitlin S., Liu J. P., Chapman D. L., Papaioannou V. E., and Efstratiadis A. (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat. Genet. 11, 155–163.
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MacDonald, M.E., Gines, S., Gusella, J.F. et al. Huntington’s Disease. Neuromol Med 4, 7–20 (2003). https://doi.org/10.1385/NMM:4:1-2:7
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DOI: https://doi.org/10.1385/NMM:4:1-2:7