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Gene Review

Htt  -  huntingtin

Mus musculus

Synonyms: AI256365, C430023I11Rik, HD, HD protein homolog, Hd, ...
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Disease relevance of Hdh


Psychiatry related information on Hdh


High impact information on Hdh


Chemical compound and disease context of Hdh


Biological context of Hdh

  • Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice [17].
  • This study excludes both Fgfr3 and Hdh as candidate genes for tlt and identifies closely linked microsatellite markers that will be useful for the positional cloning of tlt [18].
  • To determine the contribution of the polyQ stretch to normal htt function, we have generated mice with a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene (Hdh(DeltaQ)) [19].
  • Taken altogether, these results suggest that htt's polyQ stretch is required for modulating longevity in culture and support the hypothesis that the polyQ stretch may also modulate a htt function involved in regulating energy homeostasis [19].
  • The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood [20].

Anatomical context of Hdh


Associations of Hdh with chemical compounds

  • Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release [22].
  • Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death [20].
  • In order to facilitate studies of pathogenesis and therapeutics, we have generated a new inducible mouse model of HD expressing full-length huntingtin (Htt) using a tetracycline-regulated promoter [4].
  • In double transgenic mice Htt was expressed widely in the brain under the control of the tet-transactivator (tTA) driven by the prion promoter PrP (in the absence of doxycycline) [4].
  • Thus, somatic HD CAG instability appears to be a consequence of a striatal-selective disease process that accelerates the timing of an early disease phenotype, via expansion of the glutamine tract in mutant huntingtin [25].
  • Although huntingtin is cytoprotective in wild-type cells that are exposed to TNFalpha, it has no significant benefit in TNFalpha-treated cells with Pak2 knockdown [26].

Physical interactions of Hdh


Enzymatic interactions of Hdh

  • We detect caspase-cleaved htt in control human brain as well as in HD brains with early grade neuropathology, including one homozygote [29].
  • Compared with the full-length huntingtin, the caspase 3-cleaved N-htt fragments, especially the mutant fragment, preferentially segregated with the membrane fraction [30].

Co-localisations of Hdh

  • Of these interacting chaperones, only Hdj-2 and Hsc70 frequently (Hdj-2 > Hsc70) co-localize with both the aggregates in the cellular model and with the NIs in the brains of HD exon 1 transgenic mice [31].

Regulatory relationships of Hdh

  • Underscoring the relevancy of these findings, recent results suggest that caspase-1 is activated in brains of humans with HD [32].
  • Therefore, aberrant NF-kappaB activation may contribute to the neurodegeneration induced by mutant Htt [28].
  • Moreover, in acute striatal slice cultures, inhibition of IKK activity with an N-terminally truncated form of IKKgamma blocks mutant Htt-induced toxicity in medium-sized spiny neurons (MSNs) [28].
  • Curcumin also causes rapid proteasomal malfunction in the mutant huntingtin expressing cells in comparison with normal glutamine repeat expressing cells [33].

Other interactions of Hdh

  • Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin [10].
  • Loss of HAP-1 expression did not alter the gross brain expression levels of its interacting partners, huntingtin and p150glued [34].
  • Moreover, quantitative RT-PCR assays for the human homologue demonstrated elevated Rrs1 mRNA in HD compared with control postmortem brain [17].
  • In addition, we found that calpain- and caspase-derived Htt fragments preferentially accumulate in the nucleus without the requirement of further cleavage into smaller fragments [3].
  • Caspase inhibition is a therapeutic strategy that merits evaluation in humans with HD [32].

Analytical, diagnostic and therapeutic context of Hdh


  1. Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Wheeler, V.C., Gutekunst, C.A., Vrbanac, V., Lebel, L.A., Schilling, G., Hersch, S., Friedlander, R.M., Gusella, J.F., Vonsattel, J.P., Borchelt, D.R., MacDonald, M.E. Hum. Mol. Genet. (2002) [Pubmed]
  2. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Gauthier, L.R., Charrin, B.C., Borrell-Pagès, M., Dompierre, J.P., Rangone, H., Cordelières, F.P., De Mey, J., MacDonald, M.E., Lessmann, V., Humbert, S., Saudou, F. Cell (2004) [Pubmed]
  3. Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. Gafni, J., Hermel, E., Young, J.E., Wellington, C.L., Hayden, M.R., Ellerby, L.M. J. Biol. Chem. (2004) [Pubmed]
  4. Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin. Tanaka, Y., Igarashi, S., Nakamura, M., Gafni, J., Torcassi, C., Schilling, G., Crippen, D., Wood, J.D., Sawa, A., Jenkins, N.A., Copeland, N.G., Borchelt, D.R., Ross, C.A., Ellerby, L.M. Neurobiol. Dis. (2006) [Pubmed]
  5. Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis. Ryan, A.B., Zeitlin, S.O., Scrable, H. Neurobiol. Dis. (2006) [Pubmed]
  6. Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington's disease transgenic mice. Pang, T.Y., Stam, N.C., Nithianantharajah, J., Howard, M.L., Hannan, A.J. Neuroscience (2006) [Pubmed]
  7. Distinct behavioral and neuropathological abnormalities in transgenic mouse models of HD and DRPLA. Schilling, G., Jinnah, H.A., Gonzales, V., Coonfield, M.L., Kim, Y., Wood, J.D., Price, D.L., Li, X.J., Jenkins, N., Copeland, N., Moran, T., Ross, C.A., Borchelt, D.R. Neurobiol. Dis. (2001) [Pubmed]
  8. Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length. Hansson, O., Castilho, R.F., Korhonen, L., Lindholm, D., Bates, G.P., Brundin, P. J. Neurochem. (2001) [Pubmed]
  9. Impaired synaptic plasticity in mice carrying the Huntington's disease mutation. Usdin, M.T., Shelbourne, P.F., Myers, R.M., Madison, D.V. Hum. Mol. Genet. (1999) [Pubmed]
  10. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Graham, R.K., Deng, Y., Slow, E.J., Haigh, B., Bissada, N., Lu, G., Pearson, J., Shehadeh, J., Bertram, L., Murphy, Z., Warby, S.C., Doty, C.N., Roy, S., Wellington, C.L., Leavitt, B.R., Raymond, L.A., Nicholson, D.W., Hayden, M.R. Cell (2006) [Pubmed]
  11. Polyglutamine expansion of huntingtin impairs its nuclear export. Cornett, J., Cao, F., Wang, C.E., Ross, C.A., Bates, G.P., Li, S.H., Li, X.J. Nat. Genet. (2005) [Pubmed]
  12. In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets. Zhai, W., Jeong, H., Cui, L., Krainc, D., Tjian, R. Cell (2005) [Pubmed]
  13. Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease. Saydoff, J.A., Garcia, R.A., Browne, S.E., Liu, L., Sheng, J., Brenneman, D., Hu, Z., Cardin, S., Gonzalez, A., von Borstel, R.W., Gregorio, J., Burr, H., Beal, M.F. Neurobiol. Dis. (2006) [Pubmed]
  14. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X.J., Mattson, M.P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  15. Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Chuang, D.M. Critical reviews in neurobiology. (2004) [Pubmed]
  16. Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenic mice expressing a caspase-1 dominant-negative mutant. Andreassen, O.A., Ferrante, R.J., Hughes, D.B., Klivenyi, P., Dedeoglu, A., Ona, V.O., Friedlander, R.M., Beal, M.F. J. Neurochem. (2000) [Pubmed]
  17. Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice. Fossale, E., Wheeler, V.C., Vrbanac, V., Lebel, L.A., Teed, A., Mysore, J.S., Gusella, J.F., MacDonald, M.E., Persichetti, F. Hum. Mol. Genet. (2002) [Pubmed]
  18. High-resolution mapping of tlt, a mouse mutant lacking otoconia. Ying, H.C., Hurlé, B., Wang, Y., Bohne, B.A., Wuerffel, M.K., Ornitz, D.M. Mamm. Genome (1999) [Pubmed]
  19. Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro. Clabough, E.B., Zeitlin, S.O. Hum. Mol. Genet. (2006) [Pubmed]
  20. Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Hermel, E., Gafni, J., Propp, S.S., Leavitt, B.R., Wellington, C.L., Young, J.E., Hackam, A.S., Logvinova, A.V., Peel, A.L., Chen, S.F., Hook, V., Singaraja, R., Krajewski, S., Goldsmith, P.C., Ellerby, H.M., Hayden, M.R., Bredesen, D.E., Ellerby, L.M. Cell Death Differ. (2004) [Pubmed]
  21. Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. Schilling, G., Savonenko, A.V., Klevytska, A., Morton, J.L., Tucker, S.M., Poirier, M., Gale, A., Chan, N., Gonzales, V., Slunt, H.H., Coonfield, M.L., Jenkins, N.A., Copeland, N.G., Ross, C.A., Borchelt, D.R. Hum. Mol. Genet. (2004) [Pubmed]
  22. Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release. Li, H., Wyman, T., Yu, Z.X., Li, S.H., Li, X.J. Hum. Mol. Genet. (2003) [Pubmed]
  23. Reduced expression of the TrkB receptor in Huntington's disease mouse models and in human brain. Ginés, S., Bosch, M., Marco, S., Gavaldà, N., Díaz-Hernández, M., Lucas, J.J., Canals, J.M., Alberch, J. Eur. J. Neurosci. (2006) [Pubmed]
  24. Huntingtin is localized in the nucleus during preimplanatation embryo development in mice. Jeong, S.J., Kim, M., Chang, K.A., Kim, H.S., Park, C.H., Suh, Y.H. Int. J. Dev. Neurosci. (2006) [Pubmed]
  25. Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Wheeler, V.C., Lebel, L.A., Vrbanac, V., Teed, A., te Riele, H., MacDonald, M.E. Hum. Mol. Genet. (2003) [Pubmed]
  26. Huntingtin promotes cell survival by preventing Pak2 cleavage. Luo, S., Rubinsztein, D.C. J. Cell. Sci. (2009) [Pubmed]
  27. Overexpression and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase in a transgenic mouse model of Huntington's disease. Senatorov, V.V., Charles, V., Reddy, P.H., Tagle, D.A., Chuang, D.M. Mol. Cell. Neurosci. (2003) [Pubmed]
  28. Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. Khoshnan, A., Ko, J., Watkin, E.E., Paige, L.A., Reinhart, P.H., Patterson, P.H. J. Neurosci. (2004) [Pubmed]
  29. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. Wellington, C.L., Ellerby, L.M., Gutekunst, C.A., Rogers, D., Warby, S., Graham, R.K., Loubser, O., van Raamsdonk, J., Singaraja, R., Yang, Y.Z., Gafni, J., Bredesen, D., Hersch, S.M., Leavitt, B.R., Roy, S., Nicholson, D.W., Hayden, M.R. J. Neurosci. (2002) [Pubmed]
  30. 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. Kim, Y.J., Yi, Y., Sapp, E., Wang, Y., Cuiffo, B., Kegel, K.B., Qin, Z.H., Aronin, N., DiFiglia, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  31. Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Jana, N.R., Tanaka, M., Wang, G., Nukina, N. Hum. Mol. Genet. (2000) [Pubmed]
  32. Caspases in Huntington's disease. Sanchez Mejia, R.O., Friedlander, R.M. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. (2001) [Pubmed]
  33. Curcumin enhances the polyglutamine-expanded truncated N-terminal huntingtin-induced cell death by promoting proteasomal malfunction. Dikshit, P., Goswami, A., Mishra, A., Nukina, N., Jana, N.R. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  34. Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior. Chan, E.Y., Nasir, J., Gutekunst, C.A., Coleman, S., Maclean, A., Maas, A., Metzler, M., Gertsenstein, M., Ross, C.A., Nagy, A., Hayden, M.R. Hum. Mol. Genet. (2002) [Pubmed]
  35. Inactivation of the Huntington's disease gene (Hdh) impairs anterior streak formation and early patterning of the mouse embryo. Woda, J.M., Calzonetti, T., Hilditch-Maguire, P., Duyao, M.P., Conlon, R.A., MacDonald, M.E. BMC Dev. Biol. (2005) [Pubmed]
  36. Biochemical, ultrastructural, and reversibility studies on huntingtin filaments isolated from mouse and human brain. Díaz-Hernández, M., Moreno-Herrero, F., Gómez-Ramos, P., Morán, M.A., Ferrer, I., Baró, A.M., Avila, J., Hernández, F., Lucas, J.J. J. Neurosci. (2004) [Pubmed]
  37. Fast transport and retrograde movement of huntingtin and HAP 1 in axons. Block-Galarza, J., Chase, K.O., Sapp, E., Vaughn, K.T., Vallee, R.B., DiFiglia, M., Aronin, N. Neuroreport (1997) [Pubmed]
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