Genetics, Pathology, & Potential Future Advances in the Study of Huntington's Disease
Since the discovery of the HD gene in 1993, much progress into the way the disease manifests has been made. The roles of the wild-type protein have been researched extensively and it is clear that the protein is key in many aspects of human life. The exact pathogenic mechanisms of the disease are still not completely clear, but it is apparent that the toxic mutant protein induces massive neuronal cell death leading to the observed symptoms. One key question that needs answering regards inclusion bodies- are they pathogenic, or a cellular defence mechanism. If this puzzle can be solved, it will provide clear focus for future research..
The lack of an effective animal model that contains the entire Htt gene with an expanded polyQ repeat and shows a slow disease progression is affecting the chances of current treatment research being transferred to human patients. If a non-human primate model with the above phenotype can be developed, this will greatly enhance the chances of treatments entering widespread use.
The sheer volume of research into treatment provides a positive outlook for the future. While many therapies are experimental, in the next decade, drugs could become licensed to improve the quality of life of patients and in some cases, even prevent the appearance of symptoms. Personalised medicine, such as the mentioned RNAi therapy for specific SNPs in a person’s Htt gene, will become important in many conditions in the future, and is clearly an area where further research could result in many saved lives. Huntington’s disease is no longer an unknown condition attributed to being possessed by demons but is instead becoming manageable and, hopefully one day, treatable.
Adams, J. (2003). The proteasome: structure, function, and role in the cell. Cancer Treatment Reviews, 29, 3-9.
Almqvist, E., Bloch, M., Brinkman, R., & Crauford, D. H. (1999). A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease. American Journal of Human Genetics, 64, 1293-1304.
Andrade, M., & Bork, P. (1995). HEAT repeats in the Huntington's disease protein. Nature Genetics, 11, 115-116.
Arrasate, M., Mitra, S., Schweitzer, E., Segal, M., & Finkbeiner, S. (2004). Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature, 431, 805-810.
Aziz, N., Swaab, D., Pjil, H., & Roos, R. (2007). Hypothalamic dysfunction and neuroendocrine and metabolic alterations in Huntington's disease: clinical consequences and therapeutic implications. Reviews in Neuroscience, 18, 223-251.
Aziz, N., van der Burg, J., Landwhermeyer, G., Brundin, P., Stijnen, T., & Roos, R. (2008). Weight loss in Huntington's disease increases with higher CAG repeat number. Neurology, 71, 1506-1513.
Beister, A., Kraus, P., Kuhn, W., Dose, M., Weindl, A., & Gerlach, M. (2004). The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease. Journal of Neural Transmission. Supplementum, 68, 117-122.
Bennett, E., Bence, N. J., & Kopito, R. (2005). Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Molecular Cell, 17, 351-365.
Biglan, K., Zhang, Y., Long, J., Geschwind, M., Kang, G., & Killoran, A. (2013). Refining the diagnosis of Huntington's disease: the PREDICT-HD study. Frontiers in Aging Neuroscience, 5, 12.
Boudreau, R., McBride, J., Martins, I., Shen, S., Xing, Y., & Carter, B. (2009). Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Molecular Therapy, 17, 1053-1063.
Boutell, J., Thomas, P., Neal, J., Weston, V., Duce, J., & Harper, P. (1999). Aberrant interactions of transcriptional repressor proteins with the Huntington's disease gene product, huntingtin. Human Molecular Genetics, 8, 1647-1655.
Browne, S., Bowling, A., MacGarvey, U., Baik, M., Berger, S., & Muqit, M. (1997). Oxidative damage and metabolic dysfunction in Huntington's disease: selective vunerability of the basal ganglia. Annals of Neurology, 41, 646-653.
Carmichael, J., Chattelier, J., Woolfson, A., Milstein, C., Fersht, A., & Rubinsztein, D. (2000). Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease. Proceedings of the National Academy of Science, 97, 9701-9705.
Cattaneo, E., Zuccato, C., & Tartari, M. (2005). Normal huntingtin function: an alternative approach to Huntington's disease. Nature Reviews Neuroscience, 6, 919-930.
Caviston, J., & Holzbaur, E. (2009). Huntingtin as an essential integrator of intracellular vesicle trafficking. Trends in Cell Biology, 19, 147-155.
Caviston, J., Ross, J., Antony, S., Tokito, M., & Holzbaur, E. (2007). Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proceedings of the National Academy of Science, 104, 10045-10050.
Chen, J., Ondo, W., Dashtipour, K., & Swope, D. (2012). Tetrabenazine for the treatment of hyperkinetic movement disorders: a review of the literature. Clinical Therapeutics, 34, 1487-1504.
Choo, Y., Johnson, G., MacDonald, M., Detloff, P., & Lesort, M. (2004). Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Human Molecular Genetics , 13, 1407-1420.
Colin, E., Zana, D., Liot, G., Rangone, H., Borrell- Pages, M., & Li, X. (2008). Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. The EMBO Journal, 27, 2124-2134.
Cummings, C., Sun, Y., Opal, P., Antallfy, B., Mestril, R., & Orr, H. (2001). Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Human Molecular Genetics, 10, 1511-1518.
Davenport, C. (1911). Hereditary in Relation to Eugenics (1st ed.). New York: New York H. Holt.
Diaz-Hernandez, M., Hernandez, F., Martin-Aparicio, E., Gomez-Ramos, P., Moran, M., & Castano, J. (2003). Neuronal induction of the immunoproteasome in Huntington's disease. Journal of Neuroscience, 23, 11653-11661.
Diaz-Hernandez, M., Valera, A., Moran, M., Gomez-Ramos, P., Alvarez-Castelao, B., & Castano, J. (2006). Inhibition of 26S proteasome activity by huntingtin filaments but not inclusion bodies isolated from mouse and human brain. Journal of Neurochemistry, 98, 1585-1596.
DiFiglia, M., Sapp, E., Chase, K., Davies, S., Bates, G., & Vonsattel, J. (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystophic neurites in brain. Science, 277, 1990-1993.
DiFiglia, M., Sena-Esteves, M., Chase, K., Sapp, E., Pfister, E., & Sass, M. (2007). Therpeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral defects. Proceedings of the National Academy of Sciences, 104, 17204-17209.
Dinq, Q., Lewis, J., Strum, K., Dimayuga, E., Bruce-Keller, A., & J, D. (2002). Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival. Journal of Biological Chemistry, 277, 13935-13942.
Dragatsis, I., Levine, M., & Zeitlin, S. (2000). Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nature Genetics, 26, 300-306.
Dragileva, E., Hendricks, A., Teed, A., Gillis, T., Lopez, E., & Friedberg, E. (2009). Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. Neurobiology Disorders, 33, 37-47.
Dunaw, J., Jeong, H., Griffin, A., Kim, Y., Standaert, G., & Hersch, M. (2002). Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science, 296, 2238-2243.
Duyao, M., Auerbach, A., Ryan, A., Persichetti, F., Barnes, G., & McNeil, S. (1995). Inactivation of the mouse Huntington's disease gene homolog Hdh. Science, 269, 407-410.
Evers, M., Tran, H., Zalachoras, I., Meijer, O., den Dunnen, J., & van Ommen, G. (2014). Preventing formation of toxic N-terminal fragments through antisense oligonucleotide-mediated protein modification. Nucleic Acid Therapeutics, 24, 4-12.
Faber, P., Alter, J., Macdonald, M., & Hart, A. (1999). Polyglutamine mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proceedings of the National Academy of Science, 96, 179-184.
Fischer, U., Janssen, K., & Schulze-Osthoff, K. (2007). Does caspase inhibtion promote clonogenic tumor growth. Cell Cycle, 6, 3048-3053.
Frank, S. (2014). Treatment of Huntington's disease. Neurotherapeutics, 11, 153-160.
Frank, S., Ondo, W., Fahn, S., Hunter, C., Oakes, D., & Plumb, S. (2008). A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clinical Neuropharmacology, 31, 127-133.
Gines, S., Seong, I., Fossale, E., Ivanova, E., Trettel, F., & Gusella, J. (2003). Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Human Molecular Genetics, 12, 497-508.
Graham, R., Deng, Y., Slow, E., Haigh, B., Bissada, N., & Lu, G. (2006). Cleavage at the caspase 6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell, 125, 1179-1191.
Gu, M., Gash, M., Mann, V., Javoy-Aqid, F., Cooper, J., & Schapira, A. (1996). Mitochondrial defect in Huntington's disease caudate nucleus. Annals of Neurology, 39, 385-389.
Guo, J., Fisher, K., Darcey, R., Cryen, J., & O'Driscoll, C. (2010). Therapeutic targeting in the silent era: advances in non-viral siRNA delivery. Molecular BioSystems, 6, 1143-1161.
Guzhova, I., Lazarev, V., Kaznacheeva, A., Ippolitova, M., Muronetz, V., & Kinev, A. (2011). Novel mechanism of Hsp70 chaperone-mediated prevention of polyglutamine aggregates in a cellular model of Huntington's disease. Human Molecular Genetics, 20, 3953-3963.
Hansson, O., Nylandsted, J., Castilho, R., Leist, M., Jaattela, M., & Brundin, P. (2003). Overexpression of heat shock protein 70 in R6/2 Huntington’s disease mice has only modest effects on disease progression. Brain Research, 970, 47-57.
Harper, P. (1992). The epidemiology of Huntington's disease. Human Genetics, 89, 365-376.
HD iPSC Consortium. (2012). Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell, 11, 264-278.
Heemskerk, A., & Roos, R. (2012). Aspiration pneumonia and death in Huntington's disease. PLoS Currents, 1, RRN1293.
Hu, J., Matsui, M., Gagnon, K., Schwartz, J., Gabillet, S., & Arar, K. (2009). Inhibiting expression of mutant huntingtin and ataxin-3 by targetting expanded CAG repeat RNAs. Nature Biotechnology, 27, 478-484.
Huang, E., & Reichardt, L. (2001). Neurotrophins: Role in neuronal development and function. Annual Reviews in Neuroscience, 24, 677-736.
Huntington Study Group. (1996). Unified Huntington's Disease Rating Scale: Reliability and Consistency. Movement Disorders, 11, 136-142.
Huntington Study Group. (2006). Tetrabenazine as antichorea therapy in Huntington's disease. Neurology, 66, 366-372.
Huntington, G. (1872). On Chorea. Medical and Surgical Reporter of Philadelphia, 26, 317-321.
Huntington's Disease Collaborative Research Project. (1993). A novel gene containing a trinucelotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 72, 971-983.
Im, W., Ban, J., Lim, J., Lee, M., Lee, S., & Soo, K. (2013). Extracts of adipose derived stem cells slows progression in the R6/2 model of Huntington's disease. PLOS ONE, 8, e59438.
Imarisio, S., Carmichael, J., Korolchuk, V., Chen, C., Saiki, S., & Rose, C. (2008). Huntington's disease: from pathology and genetics to potential therapies. Biocemical Journal, 412, 191-209.
International Huntington Association. (1994). Guidelines for the molecular genetics predictive test in Huntington's disease. Neurology, 44, 1533-1536.
Jackson, G., Salecker, I., Dong, X., Yao, X., Arnheim, N., & Faber, P. (1998). Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron, 21, 633-642.
Jacobsen, J., Bawden, C., Rudiger, S., McLaughlan, C., Reid, S., & Waldvogel, H. (2010). An ovine transgenic Huntington’s disease model. Human Molecular Genetics, 19, 1873-1882.
Julien, C., Thompson, J., Wild, S., Yardumian, P., Snowden, J., & Turner, G. (2007). Psychiatric disorders in preclinical Huntington's disease. Journal of Neurology, Neurosurgery and Psychiatry, 78, 939-943.
Kornhuber, J., Weller, M., Schoppmeyer, K., & Riederer, P. (1994). Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. Journal of Neural Transmission: Supplementation, 43, 91-104.
Kovtun, I., Liu, Y., Bjoras, M., Klungland, A., Wilson, S., & McMurray, C. (2007). OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature, 447, 447-452.
Landles, C., & Bates, G. (2004). Huntingtin and the molecular pathogenesis of Huntington's disease. EMBO Reports, 5, 958-963.
Langbehn, D., Brinkman, R., Falush, D., Paulsen, J., & Hayden, M. (2004). A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clinical Genetics, 65, 266-267.
Lee, S., Cho, K., Jung, K., Im, W., Park, J., & Lim, H. (2009). Slowed progression in models of Huntington's disease by adipose stem cell transplantation. Annals of Neurology, 66, 671-681.
Li, H., Li, S., Yu, Z., Shelbourne, P., & Li, X. (2001). Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. Journal of Neuroscience, 21, 8473-8481.
Li, J., Popovic, N., & Brundin, P. (2005). The use of the R6 transgenic mouse models of Huntington's disease in attempts to develop novel therapeutic strategies. Journal of the American Society for Experimental Neurotherapeutics, 2, 447-464.
Li, S., & Li, X. (2006). Multiple pathways contribute to the pathogenesis of Huntington's disease. Molecular Neurodegeneration, 1, 19.
Li, W., Serpell, L., Carter, W., Ruiensztein, D., & Huntington, J. (2006). Expression and characterisation of full length human huntingtin, an elongated HEAT repeat protein. Journal of Biological Chemistry, 281, 15916-15922.
Li, Z., Karlovich, C., Fish, M., Scott, M., & Myers, R. (1999). A putative Drosophila homolog of the Huntington’s disease gene. Human Molecular Genetics, 8, 1807-1815.
Lin, Y., & Wilson, J. (2007). Trascription induced CAG repeat contraction in human cells is mediated in part by transcription coupled nucleotide excision repair. Molecular & Cellular Biology, 27, 6209-6217.
Lin, Y., Chern, Y., Shen, C., Wen, H., Chagn, Y., & Li, H. (2011). Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington's disease mouse models. PLoS One, 6, e22924.
Lombardi, M., Jaspers, L., Spronkmans, C., Gellera, C., Taroni, F., & Di Maria, E. (2009). A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference. Experimental Neurology, 217, 312-319.
Lopatina, T., Kalinina, N., Karagyuar, M., Stambolsky, D., Rubina, K., & Revischin, A. (2011). Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLOS ONE, 6, e17899.
Lovestone, S., Hodgson, S., Sham, P., Differ, A., & Levy, R. (1996). Familial psychiatric presentation of Huntington's disease. Journal of Medical Genetics, 33, 128-131.
Lucetti, C., Gambacinni, G., Bernardini, S., Dell'Agnello, G., Petrozzi, L., & Rossi, G. (2002). Amantadine in Huntington’s disease: open-label video-blinded study. Neurological Sciences, 23, 83-84.
Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., & Hetherington, C. (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.
McBride, H., Neuspiel, M., & Wasiak, S. (2006). Mitochondria: more than just a powerhouse. Current Biology, 16, 551-560.
McGeer, E., & McGeer, P. (1976). Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids. Nature, 263, 517-519.
McGill, J., & Beal, M. (2006). PGC-1alpha, a new therapeutic target in Huntington's disease. Cell, 127, 465-468.
McMurray, C. (2010). Mechanisms of trinucleotide repeat instability during human development. Nature Reviews Genetics, 11, 786-799.
Milakovic, T., & Johnson, G. (2005). Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant Huntingtin. Journal of Biological Chemistry, 280, 30773-30782.
Millipore. (2014). Anti-Huntingtin protein antibody, clone mEM48. Retrieved 03 06, 2014, from http://www.millipore.com/catalogue/item/mab5374
Morton, J., Wood, N., Hastings, M., Hurelbrink, C., Barker, R., & Maywood, E. (2005). Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease. Journal of Neuroscience, 25, 157-163.
Niclis, J., Trounson, A., Dottori, M., Ellisdon, A., Bottomley, S., & Verlinksy, Y. (2009). Human embryonic stem cell models of Huntington's disease. Reproductive Biomedicine Online, 19, 106-113.
Ona, V., Li, M., Vonsattel, J., Andrews, L., Khan, S., & Chung, W. (1999). Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature, 399, 263-267.
O'Suilleabhain, P., & Dewey, R. (2003). A randomised trial of amantadine in Huntington's disease. Archives of Neurology, 60, 996-998.
Pal, E., Severin, F., Lommer, B., Shevchenko, A., & Zerial, M. (2006). Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease. Journal of Cell Biology, 72, 605-618.
Panov, A., Lund, S., & Greenamyre, J. (2005). Ca2+-induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington's disease individuals. Molecular & Cellular Biochemistry, 269, 143-152.
Perluigi, M., Poon, H., Maragos, W., Pierce, W., Klein, J., & Calabrese, V. (2005). Proteomic analysis of protein expression and oxidative modification in R6/2 trangenic mice. Molecular & Cellular Proteomics, 4, 1849-1861.
Perrin, V., Regulier, E., Abbas-Terki, T., Hassig, R., Brouillet, E., & Aebischer, P. (2007). Neuroprotection by Hsp104 and Hsp27 in lentiviral-based rat models of Huntington's disease. Molecular Therapy, 15, 903-911.
Pfister, E., & Zamore, P. (2009). Huntington's disease: silencing a brutal killer. Experimental Neurology, 220, 226-229.
Polidori, M., Mecocci, P., Browne, S., Senin, U., & Beal, M. (1999). Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex. Neuroscience Letters, 272, 53-56.
Pouladi, M., Morton, J., & Hayden, M. (2013). Choosing an animal model for the study of Huntington's disease. Nature Reviews Neuroscience, 14, 708-721.
Ravikumar, B., Vacher, C., Berger, Z., Davies, J., Lou, S., & Oroz, L. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington's disease. Nature Genetics, 36, 585-595.
Reddy, P., Charles, V., Williams, M., Miller, G., Whetsell, W., & Tagle, D. (1999). Transgenic mice expressing mutated full-length HD cDNA: a paradigm for locomotor changes and selective neuronal loss in Huntington's disease. Philosophical Transactions of the Royal Society of London Biological Sciences, 354, 1035-1045.
Ridley, R., Frith, C., Crow, T., & Conneally, P. (1988). Anticipation in Huntington's disease is inherited through the male line but may originate in the female. Journal of Medical Genetics, 25, 589-595.
Riener, A., Dragatsis, I., Zeitlin, S., & Goldowitz, D. (2003). Wild-type Huntingtin plays a role in brain development and neuronal survival. Molecular Neurobiology, 28, 259-275.
Rigamonti, D., Bauer, J., De-Fraja, C., Conti, L., Sipione, S., & Sciorati, C. (2000). Wild-type Huntingtin protects from apoptosis upstream of caspase-3. Journal of Neuroscience, 20, 3705-3713.
Roos, R. (2010). Huntington's disease: a clinical review. Orphanet Journal of Rare Diseases, 5, 40.
Rosenblatt, A. (2007). Understanding the psychiatric prodome of Huntington's disease. Journal of Neurology, Neurosurgery and Psychiatry, 78, 913.
Ross, C., & Tabrizi, S. (2011). Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurology, 10, 83-98.
Rossignol, J., Boyer, C., Leveque, X., Finq, K., Thinard, R., & Blanchard, F. (2011). Mesenchymal stem cell transplantation and DMEM administration in a 3NP rat model of Huntington's disease: morphological and behavioural outcomes. Behavioural Brain Research, 217, 369-378.
Rossignol, J., Fink, K., Davies, K., Clerc, S., Crane, A., & Matchynski, J. (2014). Transplant of adult mesenchymal and neural stem cells provide neuroprotection and behavioural sparing in a transgenic rat model of Huntington's disease. Stem Cells, 32, 500-509.
Ryu, J., Kim, J., Cho, S., Hatori, K., Nagai, A., & Choi, H. (2004). Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease. Neurobiology of Disease, 16, 68-77.
Saxton, W., & Hollenbeck, P. (2012). The axonal transport of mitochondria. Journal of Cell Biology, 125, 2095-2104.
Schwarz, D., Hutvagner, G., Du, T., Xu, Z., Aronin, N., & Zamore, P. (2003). Asymmetry in the assembly of the RNAi enzyme complex. Cell, 115, 199-208.
Sieradzan, K., Mechan, A., Jones, L., Wanker, E., Nukina, N., & Mann, D. (1999). Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Experimental Neurology, 156, 92-99.
Slow, E., Graham, R., Osmand, A., Devon, R., Lu, G., & Deng, G. (2005). Absence of behavioural abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proceedings of the National Academy of Science, 102, 11402-11407.
Stefan, J., Kazantsev, A., Spasiv-Boscovic, O., Greenwald, M., Zhu, Y., & Gohler, H. (2000). The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proceedings of the National Academy of Science, 97, 6763-6768.
Strachan, T., & Read, A. (2011). Human Molecular Genetics. In E. Owen (Ed.). Garland Science.
Summerton, J. (2007). Morpholino, siRNA and S-DNA compared: impact of structure and mechanism of action on off-target effects and sequence specificity. Current Topics in Medicinal Chemistry, 7, 651-660.
Tabrizi, S., Reilmann, R., Roos, R., Durr, A., Leavitt, B., & Owen, G. (2012). Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurology, 11, 42-53.
Takano, H., & Gusella, J. (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. Biomed Central Neuroscience, 3, 15.
Tian, J., Yan, Y., Zhou, R., Lou, H., Rong, Y., & Zhang, B. (2014). Soluble N-terminal fragment of mutant huntingtin protein impairs mitochondrial axonal transport in cultured hippocampal neurons. Neuroscience Bulletin, 30, 74-80.
Tomar, R., Matta, H., & Chaudhary, P. (2003). Use of adeno-associated viral vector for delivery of small interfering RNA. Oncogene, 22, 5712-5715.
Tyagi, S., Tyagi, L., Shekhar, R., Singh, M., & Kori, M. (2010). Symptomatic treatment and management of Huntington's disease: an overview. Global Journal of Pharmacology, 4, 6-12.
Vacher, C., Garcia-Oroz, L., & Rubinsztein, D. (2005). Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease. Human Molecular Genetics, 14, 3425-3433.
van Wamelen, D., Aziz, N., Anink, J., Steenhoven, R., Angeloni, D., & Fraschini, F. (2013). Suprachiasmatic nucleus neuropeptide expression in patients with Huntington's disease. Sleep, 36, 117-125.
Venkatraman, P., Wetzel, R., Tanaka, M., Nukina, N., & Goldberg, A. (2004). Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Molecular Cell, 14, 95-104.
Violante, V., Luongo, A., Pepe, I., Annunziata, S., & Gentile, V. (2001). Transglutaminase-dependent formation of protein aggregates as possible biochemical mechanism for polyglutamine diseases. Brain Research Bulletin, 56, 169-172.
Walker, F. (2007). Huntington's disease. The Lancet, 369, 218-228.
Warby, S., Montpetit, A., Hayden, A., Carroll, J., Butland, S., & Visscher, H. (2009). CAG expansion in the Huntington disease gene is associated with a specific and targettable predisposing haplogroup. The American Journal of Human Genetics, 84, 351-366.
White, J., Auerback, W., Duyao, M., Vonsattel, J., Gusella, J., & Joyner, A. (1997). Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nature Genetics, 17, 404-410.
Whitehead, K., Langer, R., & Anderson, D. (2009). Knocking down barriers: advances in siRNA delivery. Nature Reviews Drug Discovery, 129-138.
Wilkins, A., Kemp, K., Ginty, M., Hares, K., Mallam, E., & Scolding, N. (2009). Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Research, 3, 63-70.
Yamamoto, A., Lucas, J., & Hen, R. (2000). Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell, 101, 57-66.
Yang, D., Wang, C., Zhao, B., Li, W., Ouyang, Z., & Liu, Z. (2010). Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Human Molecular Genetics, 19, 3983-3994.
Yang, S., Cheng, P., Banta, H., Piotrowska-Nitsche, K., Yang, J., & Cheng, E. (2008). Towards a transgenic model of Huntington's disease in a non-human primate. Nature, 453, 921-924.
Yang, W., Dunlap, J., Andrews, R., & Wetzel, R. (2002). Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Human Molecular Genetics, 11, 2905-2917.
Yu, J., Vodyanik, M., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J., & Tian, S. (2007). Induced pluripotent stem cell lines generated from human somatic cells. Science, 318, 1917-1920.
Zhang, S., Feany, M., Saraswati, S., Littleton, J., & Perrimon, N. (2009). Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington's disease model. Disease Models & Mechanisms, 2, 247-266.
Zhang, Y., Li, M., Drozda, M., Chen, M., Ren, S., & Mejia-Sanchez, R. (2003). Depletion of wild-type huntingtin in mouse models of neurological diseases. Journal of Neurochemistry, 87, 101-106.
Zheng, Q., & Joinnides, M. (2009). Hunting for the function of Huntingtin. Disease Models & Mechanisms, 2, 199-200.
Zhou, H., Cao, F., Wang, Z., Yu, Z., Nguyen, H., & Evans, J. (2003). Huntingtin forms toxic NH2 terminal fragment complexes that are promoted by the age-dependant decrease in proteasome activity. Journal of Cell Biology, 163, 109-118.
Zoghby, H., & Orr, H. (2000). Glutamine repeats and neurodegeneration. Annual Reviews in Neuroscience, 23, 217-247.
Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., & Conti, L. (2003). Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature Genetics, 35, 76-83.