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Screening of Therapeutic Strategies for Huntington's Disease in YAC128 Transgenic Mice
Article first published online: 16 FEB 2011
DOI: 10.1111/j.1755-5949.2011.00246.x
© 2011 Blackwell Publishing Ltd
Additional Information
How to Cite
Gil-Mohapel, J. M. (2012), Screening of Therapeutic Strategies for Huntington's Disease in YAC128 Transgenic Mice. CNS Neuroscience & Therapeutics, 18: 77–86. doi: 10.1111/j.1755-5949.2011.00246.x
Publication History
- Issue published online: 26 JAN 2012
- Article first published online: 16 FEB 2011
References
- 1, . Experimental therapeutics in transgenic mouse models of Huntington's disease. Nat Rev Neurosci 2004;5:373–384.
- 2, . The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease. Brain Res Rev 2009;59:410–431.
- 3, . The use of transgenic and knock-in mice to study Huntington's disease. Cytogenet Genome Res 2003;100:276–286.
- 4, , , et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996;87:493–506.
- 5, , , , , . Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. Proc Natl Acad Sci USA 2000;97:8093–8097.
- 6, , , , , . Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington's disease. J Neurosci 2003;23:2193–2202.
- 7, , , et al. Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice. J Comp Neurol 2005;490:354–370.
- 8, . Mechanisms of neurodegeneration in Huntington's disease. Eur J Neurosci 2008;27:2803–2820.
- 9, , , et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 2008;28:6182–6195.
- 10, , , . Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease. Neuroscience 2008;157:606–620.
- 11, , , et al. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 1999;23:181–192.
- 12, , , et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 2003;12:1555–1567.
- 13, , , et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 1998;273:9158–9167.
- 14, , , et al. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J Neurosci 2002;22:7862–7872.
- 15, . Calpain activation in Huntington's disease. J Neurosci 2002;22:4842–4849.
- 16, , , , , . Inhibition of calpain cleavage of huntingtin reduces toxicity: Accumulation of calpain/caspase fragments in the nucleus. J Biol Chem 2004;279:20211–20220.
- 17, , , et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 2006;125:1179–1191.
- 18, , , et al. Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models. Neurobiol Dis 2006;21:444–455.
- 19, , , et al. Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease. J Neurochem 2005;95:210–220.
- 20, , , , , . Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease. J Neurosci 2005;25:4169–4180.
- 21, , , et al. Testicular degeneration in Huntington disease. Neurobiol Dis 2007;26:512–520.
- 22, , , et al. Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin. Brain 2009;132:919–932.
- 23, , , , . Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease. Hum Mol Genet 2005;14:3823–3835.
- 24, , , et al. Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci USA 2005;102:11402–11407.
- 25, , , et al. Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease. J Neurosci 2009;29:2193–2204.
- 26, , , et al. Glutamate receptor abnormalities in the YAC128 transgenic mouse model of Huntington's disease. Neuroscience 2007;147:354–372.
- 27, . Corticostriatal synaptic function in mouse models of Huntington's disease: Early effects of huntingtin repeat length and protein load. J Physiol 2007;585:817–831.
- 28, , , et al. Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease. J Neurosci 2009;29:2414–2427.
- 29, , , et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997;277:1990–1993.
- 30, , , et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997;90:537–548.
- 31, , , . Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998;95:55–66.
- 32, , , et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann Neurol 1999;46:842–849.
- 33, , , , . Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004;431:805–810.
- 34, , , et al. Body weight is modulated by levels of full-length huntingtin. Hum Mol Genet 2006;15:1513–1523.
- 35, , , et al. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum Mol Genet 2010;19:1528–1538.
- 36, , , et al. Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease. Hum Mol Genet 2005;14:1379–1392.
- 37, , , , . Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease. BMC Neurosci 2006;7:80–89.
- 38, , , , . Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington's disease. J Neurosci 2007;27:13614–13623.
- 39, , , et al. Polyglutamine-modulated striatal calpain activity in YAC transgenic Huntington disease mouse model: Impact on NMDA receptor function and toxicity. J Neurosci 2008;28:12725–12735.
- 40, , , et al. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 2009;15:1407–1413.
- 41, , , et al. Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice. Neuron 2010;65:178–190.
- 42, , , , , . The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease. J Neural Transm Suppl 2004;68:117–122.
- 43, , . A pilot study of the clinical efficacy and safety of memantine for Huntington's disease. Parkinsonism Relat Disord 2007;13:453–444.
- 44, , , et al. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc Natl Acad Sci USA 2005;102:2602–2607.
- 45, , , et al. Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 2003;39:227–239.
- 46, , , , . Neuroprotective effects of inositol 1,4,5-trisphosphate receptor C-terminal fragment in a Huntington's disease mouse model. J Neurosci 2009;29:1257–1266.
- 47, , , . Ginsenosides Rb1 and Rg3 protect cultured rat cortical cells from glutamate-induced neurodegeneration. J Neurosci Res 1998;53:426–432.
- 48, , , , . Inhibitory effect of ginsenosides on NMDA receptor-mediated signals in rat hippocampal neurons. Biochem Biophys Res Commun 2002;296:247–254.
- 49, , . Protective effects of ginseng components in a rodent model of neurodegeneration. Ann Neurol 2005;57:642–648.
- 50, , , et al. Protective effects of ginseng saponins on 3-nitropropionic acid-induced striatal degeneration in rats. Neuropharmacology 2005;48:743–756.
- 51, , , , , . Ginsenosides protect striatal neurons in a cellular model of Huntington's disease. J Neurosci Res 2009;87:1904–1912.
- 52, , . Transglutaminase action imitates Huntington's disease: Selective polymerization of Huntingtin containing expanded polyglutamine. Mol Cell 1998;1:595–601.
- 53, , , . Tissue transglutaminase is increased in Huntington's disease brain. J Neurochem 1999;73:2018–2027.
- 54, , . Evidence for a role for transglutaminase in Huntington's disease and the potential therapeutic implications. Neurochem Int 2002;40:31–36.
- 55, , , et al. ‘Tissue’ transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington's disease. Cell Death Differ 2002;9:873–880.
- 56, . Tissue transglutaminase contributes to disease progression in the R6/2 Huntington's disease mouse model via aggregate-independent mechanisms. J Neurochem 2005;92:83–92.
- 57, . The protective effects of cystamine in the R6/2 Huntington's disease mouse involve mechanisms other than the inhibition of tissue transglutaminase. Neurobiol Aging 2006;27:871–879.
- 58, , , et al. Tissue transglutaminase and apoptosis: Sense and antisense transfection studies with human neuroblastoma cells. Mol Cell Biol 1994;14:6584–6596.
- 59, , , et al. Transglutaminase overexpression sensitizes neuronal cell lines to apoptosis by increasing mitochondrial membrane potential and cellular oxidative stress. J Neurochem 2002;81:1061–1072.
- 60, , , , . Inhibition of ‘tissue’ transglutaminase increases cell survival by preventing apoptosis. J Biol Chem 1999;274:34123–34128.
- 61, , , , . Tissue transglutaminase does not contribute to the formation of mutant huntingtin aggregates. J Cell Biol 2001;153:25–34.
- 62, , , et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet 1998;18:111–117.
- 63, , , , . The length of polyglutamine tract, its level of expression, the rate of degradation, and the transglutaminase activity influence the formation of intracellular aggregates. Biochem Biophys Res Commun 1999;260:150–158.
- 64, , , et al. Cystamine inhibits transglutaminase and caspase-3 cleavage in glutamate-exposed astroglial cells. J Neurosci Res 2003;74:52–59.
- 65, , , , . Mutant huntingtin protein: A substrate for transglutaminase 1, 2, and 3. J Neuropathol Exp Neurol 2005;64:58–65.
- 66, , , et al. Therapeutic effects of cystamine in a murine model of Huntington's disease. J Neurosci 2002;22:8942–8950.
- 67, , , et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 2002;8:143–149.
- 68, , , et al. Cerebral PET imaging and histological evidence of transglutaminase inhibitor cystamine induced neuroprotection in transgenic R6/2 mouse model of Huntington's disease. J Neurol Sci 2005;231:57–66.
- 69, , , et al. Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation. J Neurochem 2004;91:413–422.
- 70, , , . Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem 2003;278:3825–3830.
- 71, , , et al. Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 2006;116:1410–1424.
- 72, , , et al. Treatment of YAC128 mice and their wild-type littermates with cystamine does not lead to its accumulation in plasma or brain: Implications for the treatment of Huntington disease. J Neurochem 2005;94:1087–1101.
- 73, . CYTE-I-HD: Phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington's disease. Mov Disord 2006;21:530–533.
- 74, , , et al. PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's disease. Brain 1997;120:503–514.
- 75, , , et al. Decreased striatal monoaminergic terminals in Huntington disease. Neurology 2000;54:1753–1759.
- 76, , , , . A quantitative investigation of the substantia nigra in Huntington's disease. Ann Neurol 1989;26:13–19.
- 77, , , et al. Analysis of cellular, transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology. Brain Res Mol Brain Res 2003;119:28–36.
- 78, , . The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea. Brain 2007;130:222–232.
- 79, , , et al. Nuclear and neuropil aggregates in Huntington's disease: Relationship to neuropathology. J Neurosci 1999;19:2522–2534.
- 80, , . Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease. Ann Neurol 1997;42:215–221.
- 81, , , et al. Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene. Proc Natl Acad Sci USA 1998;95:6480–6485.
- 82, , , et al. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Neurology 2005;65:941–943.
- 83, , , , . Unraveling a role for dopamine in Huntington's disease: The dual role of reactive oxygen species and D2 receptor stimulation. Proc Natl Acad Sci USA 2005;102:12218–12223.
- 84, , , . Dopamine enhances motor and neuropathological consequences of polyglutamine expanded huntingtin. FASEB J 2006;20:2541–2543.
- 85
- 86, . The use of tetrabenazine in movement disorders. Adv Clin Neurosci Rehabil 2005;5:40–41.
- 87, , , . Dopaminergic signaling and striatal neurodegeneration in Huntington's disease. J Neurosci 2007;27:7899–7910.
- 88Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology 2006;66:366–372.
- 89, . Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology 2007;68:797.
- 90, , , et al. Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum Mol Genet 2008;17:2390–2404.
- 91, , et al. Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments. Mol Cell Neurosci 2009;40:121–127.
- 92, , , et al. Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci USA 2001;98:12784–12789.
- 93, , , et al. Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Cell Death Differ 2004;11:424–438.
- 94, , , et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J Biol Chem 2000;275:19831–19838.
- 95, , , et al. Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington's disease. Neuroscience 2002;109:81–88.
- 96, , , et al. Eicosapentaenoic acid protects endothelial cells against anoikis through restoration of cFLIP. Hypertension 2003;42:342–348.
- 97, , . Eicosapentaenoic acid (EPA): An antiinflammatory omega-3 fat with potential clinical applications. Nutrition 2000;16:1116–1118.
- 98
- 99, , , et al. Mitochondrion is the principal target for nutritional and pharmacological control of triglyceride metabolism. J Lipid Res 1997;38:1851–1858.
- 100, , , et al. Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease. Exp Neurol 2005;196:266–272.
- 101, , , et al. Ethyl-EPA in Huntington disease: A double-blind, randomized placebo-controlled trial. Neurology 2005;65:286–292.
- 102, , , et al. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 2000;97:6763–6768.
- 103, , , et al. Cellular toxicity of polyglutamine expansion proteins: Mechanism of transcription factor deactivation. Mol Cell 2004;15:95–105.
- 104, , , et al. Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 2002;22:1277–1287.
- 105, , , et al. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 2002;296:2238–2243.
- 106, . Are Huntington's and polyglutamine-based ataxias proteasome storage diseases? Int J Biochem Cell Biol 2003;35:562–571.
- 107, . Polyglutamine diseases and transport problems: Deadly traffic jams on neuronal highways. Arch Neurol 2005;62:46–51.
- 108, . Intrabody applications in neurological disorders: Progress and future prospects. Mol Ther 2005;12:394–401.
- 109, . The therapeutic potential of intrabodies in neurologic disorders: Focus on Huntington and Parkinson diseases. BioDrugs 2006;20:327–333.
- 110, , , et al. Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease. Proc Natl Acad Sci USA 2001;98:4764–4769.
- 111, , , et al. Potent inhibition of huntingtin aggregation and cytotoxicity by a disulfide bond-free single-domain intracellular antibody. Proc Natl Acad Sci USA 2004;101:17616–17621.
- 112, , , et al. A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease. Neurobiol Dis 2005;19:47–56.
- 113, . A single-chain Fv intrabody provides functional protection against the effects of mutant protein in an organotypic slice culture model of Huntington's disease. Brain Res Mol Brain Res 2004;121:141–145.
- 114, , , et al. Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies. Proc Natl Acad Sci USA 2005;102:11563–11568.
- 115, , , . Combinational approach of intrabody with enhanced Hsp70 expression addresses multiple pathologies in a fly model of Huntington's disease. FASEB J 2008;22:2003–2011.
- 116, , . Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington's disease. J Neurosci 2009;29:13589–13602.

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