The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient β-cell mass and exocytosis
10.1093/hmg/ddi053
Crossref journal-article
Oxford University Press (OUP)
Human Molecular Genetics (286)
Bibliography

Björkqvist, M., Fex, M., Renström, E., Wierup, N., Petersén, Å., Gil, J., Bacos, K., Popovic, N., Li, J.-Y., Sundler, F., Brundin, P., & Mulder, H. (2005). The R6/2 transgenic mouse model of Huntington’s disease develops diabetes due to deficient β-cell mass and exocytosis. Human Molecular Genetics, 14(5), 565–574.

Authors 12
  1. Maria Björkqvist (first)
  2. Malin Fex (additional)
  3. Erik Renström (additional)
  4. Nils Wierup (additional)
  5. Åsa Petersén (additional)
  6. Joana Gil (additional)
  7. Karl Bacos (additional)
  8. Natalija Popovic (additional)
  9. Jia-Yi Li (additional)
  10. Frank Sundler (additional)
  11. Patrik Brundin (additional)
  12. Hindrik Mulder (additional)
References 51 Referenced 110
  1. Podolsky, S., Leopold N.A. and Sax D.S. ( 1972 ) Increased frequency of diabetes mellitus in patients with Huntington's chorea. Lancet , 24 , 1356 –1358. (10.1016/S0140-6736(72)91092-6)
  2. The Huntington's Disease Collaboration Group. ( 1993 ) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell , 26 , 971 –983. (10.1016/0092-8674(93)90585-E)
  3. Gutekunst, C.A., Levey, A.I., Heilman, C.J., Whaley, W.L., Yi, H., Nash, N.R., Rees, H.D., Madden, J.J. and Hersch, S.M. ( 1995 ) Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc. Natl Acad. Sci. USA , 92 , 8710 –8714. (10.1073/pnas.92.19.8710)
  4. Li, H., Li, S.H., Cheng, A.L., Mangiarini, L., Bates, G.P. and Li, X.J. ( 1999 ) Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. Hum. Mol. Genet. , 8 , 1227 –1236. (10.1093/hmg/8.7.1227)
  5. Gauthier, L.R., Charrin, B.C., Borrell-Pages, M., Dompierre, J.P., Rangone, H., Cordelieres, F.P., De Mey, J., MacDonald, M.E., Lessmann, V., Humbert, S. and Saudou, F. ( 2004 ) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell , 118 , 127 –138. (10.1016/j.cell.2004.06.018)
  6. Rigamonti, D., Bauer, J.H., De-Fraja, C., Conti, L., Sipione, S., Sciorati, C., Clementi, E., Hackam, A., Hayden, M.R., Li, Y. et al. ( 2000 ) Wild-type huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci.20 , 3705 –3713. (10.1523/JNEUROSCI.20-10-03705.2000)
  7. Rigamonti, D., Sipione, S., Goffredo, D., Zuccato, C., Fossale, E. and Cattaneo, E. ( 2001 ) Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing. J. Biol. Chem.276 , 14545 –14548. (10.1074/jbc.C100044200)
  8. Gervais, F.G., Singaraja, R., Xanthoudakis, S., Gutekunst, C.A., Leavitt, B.R., Metzler, M., Hackam, A.S., Tam, J., Vaillancourt, J.P., Houtzager, V. et al. ( 2002 ) Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat. Cell Biol.4 , 95 –105. (10.1038/ncb735)
  9. Leavitt, B.R., Guttman, J.A., Hodgson, J.G., Kimel, G.H., Singaraja, R., Vogl, A.W. and Hayden, M.R. ( 2001 ) Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo . Am. J. Hum. Genet.68 , 313 –324. (10.1086/318207)
  10. Ho, L.W., Brown, R., Maxwell, M., Wyttenbach, A. and Rubinsztein, D.C. ( 2001 ) Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington's disease. J. Med. Genet.38 , 450 –452. (10.1136/jmg.38.7.450)
  11. Zoghbi, H.Y. and Orr, H.T. ( 2000 ) Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. , 23 , 217 –247. (10.1146/annurev.neuro.23.1.217)
  12. DiFiglia, M., Sapp, E., Chase, K.O., Davies, S.W., Bates, G.P., Vonsattel, J.P. and Aronin, N. ( 1997 ) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science , 26 , 1990 –1993. (10.1126/science.277.5334.1990)
  13. Davies, S.W., Turmaine, M., Cozens, B.A., DiFiglia, M., Sharp, A.H., Ross, C.A., Scherzinger, E., Wanker, E.E., Mangiarini, L. and Bates, G.P. ( 1997 ) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell , 90 , 537 –548. (10.1016/S0092-8674(00)80513-9)
  14. Sathasivam, K., Hobbs, C., Turmaine, M., Mangiarini, L., Mahal, A., Bertaux, F., Wanker, E.E., Doherty, P., Davies, S.W. and Bates, G.P. ( 1999 ) Formation of polyglutamine inclusions in non-CNS tissue. Hum. Mol. Genet. , 8 , 813 –822. (10.1093/hmg/8.5.813)
  15. Schilling, G., Becher, M.W., Sharp, A.H., Jinnah, H.A., Duan, K., Kotzuk, J.A., Slunt, H.H., Ratovitski, T., Cooper, J.K., Jenkins, N.A. 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. (10.1093/hmg/8.3.397)
  16. Jenkins, B.G., Koroshetz, W.J., Beal, M.F. and Rosen, B.R. ( 1993 ) Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology , 43 , 2689 –2695. (10.1212/WNL.43.12.2689)
  17. Beal, M.F. ( 1995 ) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol. , 38 , 357 –366. (10.1002/ana.410380304)
  18. Nakao, N. and Brundin, P. ( 1998 ) Neurodegeneration and glutamate induced oxidative stress. Prog. Brain. Res. , 116 , 245 –263. (10.1016/S0079-6123(08)60441-0)
  19. Schilling, G., Sharp, A.H., Loev, S.J., Wagster, M.V., Li, S.H., Stine, O.C. and Ross, C.A. ( 1995 ) Expression of the Huntington's disease (IT15) protein product in HD patients. Hum. Mol. Genet. , 4 , 1365 –1371. (10.1093/hmg/4.8.1365)
  20. Mangiarini, L., Sathasivam, K., Mahal, A., Mott, R., Seller, M. and Bates, G.P. ( 1997 ) Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nat. Genet. , 15 , 197 –200. (10.1038/ng0297-197)
  21. Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S.W. and Bates, G.P. ( 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. (10.1016/S0092-8674(00)81369-0)
  22. Murphy, K.P., Carter, R.J., Lione, L.A., Mangiarini, L., Mahal, A., Bates, G.P., Dunnett, S.B. and Morton, A.J. ( 2000 ) Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation. . Neuroscience , 20 , 5115 –5123. (10.1523/JNEUROSCI.20-13-05115.2000)
  23. Petersén, Å., Gil, J., Maat-Schieman, Björkqvist, M., Tanila, H., Araújo, I.M., Smith, R., Popovic, N., Wierup, N., Norlén, P. et al. ( 2005 ) Orexin loss in Huntington's disease. Hum. Mol. Genet. , 14 , 1 –9. (10.1093/hmg/ddi004)
  24. Turmaine, M., Raza, A., Mahal, A., Mangiarini, L., Bates, G.P. and Davies, S.W. ( 2000 ) Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. Proc. Natl Acad. Sci. USA , 97 , 8093 –8097. (10.1073/pnas.110078997)
  25. Iannicola, C., Moreno, S., Oliverio, S., Nardacci, R., Ciofi-Luzzatto, A. and Piacentini, M. ( 2000 ) Early alterations in gene expression and cell morphology in a mouse model of Huntington's disease. J. Neurochem. , 75 , 830 –839. (10.1046/j.1471-4159.2000.0750830.x)
  26. Helmlinger, D., Yvert, G., Picaud, S., Merienne, K., Sahel, J., Mandel, J.L. and Devys, D. ( 2002 ) Progressive retinal degeneration and dysfunction in R6 Huntington's disease mice. Hum. Mol. Genet. , 15 , 3351 –3359. (10.1093/hmg/11.26.3351)
  27. Hurlbert, M.S., Zhou, W., Wasmeier, C., Kaddis, F.G., Hutton, J.C. and Freed, C.R. ( 1999 ) Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes , 48 , 649 –651. (10.2337/diabetes.48.3.649)
  28. Luesse, H.G., Schiefer, J., Spruenken, A., Puls, C., Block, F. and Kosinski, C.M. ( 2001 ) Evaluation of R6/2 HD transgenic mice for therapeutic studies in Huntington's disease: behavioral testing and impact of diabetes mellitus. Behav. Brain Res. , 126 , 185 –195. (10.1016/S0166-4328(01)00261-3)
  29. Andreassen, O.A., Dedeoglu, A., Stanojevic, V., Hughes, D.B., Browne, S.E., Leech, C.A., Ferrante, R.J., Habener, J.F., Beal, M.F. and Thomas, M.K. ( 2002 ) Huntington's disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression. Neurobiol. Dis. , 11 , 410 –424. (10.1006/nbdi.2002.0562)
  30. Schmued, L.C., Albertson, C. and Slikker, W. ( 1997 ) Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res. , 751 , 37 –46. (10.1016/S0006-8993(96)01387-X)
  31. Gisselsson, D., Jonson, T., Petersén, Å., Strömbeck, B., Dal Cin. P., Höglund. M., Mittelman, F., Mertens, F. and Mandahl, N. ( 2001 ) Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl Acad. Sci. USA , 98 , 12683 –12688. (10.1073/pnas.211357798)
  32. Renström, E., Eliasson, L., Bokvist, K. and Rorsman, P. ( 1996 ) Cooling inhibits exocytosis in single mouse pancreatic B-cells by suppression of granule mobilization. J. Physiol. , 494 , 41 –52. (10.1113/jphysiol.1996.sp021474)
  33. Wiser, O., Trus, M., Hernandez, A., Renström, E., Barg, S., Rorsman, P. and Atlas, D. ( 1999 ) The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc. Natl Acad. Sci. USA , 96 , 248 –253. (10.1073/pnas.96.1.248)
  34. Schulla, V., Renström, E., Feil, R., Feil, S., Franklin, I., Gjinovci, A., Jing, X.J., Laux, D., Lundquist, I., Magnuson, M.A. et al. ( 2003 ) Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice. EMBO J. , 22 , 3844 –3854. (10.1093/emboj/cdg389)
  35. Kremer, H.P., Roos, R.A., Frolich, M., Radder, J.K., Nieuwenhuijzen Kruseman, A.C., Van der Velde, A. and Buruma, O.J. ( 1989 ) Endocrine functions in Huntington's disease. A two-and-a-half years follow-up study. J. Neurol. Sci. , 90 , 335 –344. (10.1016/0022-510X(89)90120-2)
  36. Craft, S. and Watson, G.S. ( 2004 ) Insulin and neurodegenerative disorders. Lancet Neurol. , 3 , 169 –178. (10.1016/S1474-4422(04)00681-7)
  37. Ristow, M. ( 2004 ) Neurodegenerative disorders associated with diabetes mellitus. J Mol. Med. , 82 , 510 –529. (10.1007/s00109-004-0552-1)
  38. Jenkins, B.G., Klivenyi, P., Kustermann, E., Andreassen, O.A., Ferrante, R.J., Rosen, B.R. and Beal, M.F. ( 2000 ) Nonlinear decrease over time in N -acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington's disease mice. J. Neurochem. , 74 , 2108 –2119. (10.1046/j.1471-4159.2000.0742108.x)
  39. Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X.J. and Mattson, M.P. ( 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. (10.1073/pnas.0536856100)
  40. De Krijger, R.R., Aanstoot, H.J., Kranenburg, G., Reinhard, M., Visser, W.J. and Bruining, G.J. ( 1992 ) The midgestational human fetal pancreas contains cells coexpressing islet hormones. Dev. Biol. , 153 , 368 –375. (10.1016/0012-1606(92)90121-V)
  41. Samols, E. and Stagner, J.I. ( 1990 ) Islet somatostatin—microvascular, paracrine, and pulsatile regulation. Metabolism , 39 , 55 –60. (10.1016/0026-0495(90)90212-U)
  42. Butler, A.E., Janson, J., Soeller, W.C. and Butler, P.C. ( 2003 ) Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes , 52 , 2304 –2314. (10.2337/diabetes.52.9.2304)
  43. Gil, J.M., Leist, M., Popovic, N., Brundin, P. and Petersen, A. ( 2004 ) Asialoerythropoetin is not effective in the R6/2 line of Huntington's disease mice. BMC Neurosci. , 10 , 5 –17. (10.1186/1471-2202-5-17)
  44. Lazic, S.E., Grote, H., Armstrong, R.J., Blakemore, C., Hannan, A.J., van Dellen, A. and Barker, R.A. ( 2004 ) Decreased hippocampal cell proliferation in R6/1 Huntington's mice. Neuroreport , 15 , 811 –813. (10.1097/00001756-200404090-00014)
  45. Sathasivam, K., Woodman, B., Mahal, A., Bertaux, F., Wanker, E.E., Shima, D.T. and Bates, G.P. ( 2001 ) Centrosome disorganization in fibroblast cultures derived from R6/2 Huntington's disease (HD) transgenic mice and HD patients. Hum. Mol. Genet. , 10 , 2425 –2435. (10.1093/hmg/10.21.2425)
  46. Weir, G.C., Laybutt, D.R., Kaneto, H., Bonner-Weir, S. and Sharma, A. ( 2001 ) Beta-cell adaptation and decompensation during the progression of diabetes. Diabetes , 50 , S154 –S159. (10.2337/diabetes.50.2007.S154)
  47. Edwardson, J.M., Wang, C.T., Gong, B., Wyttenbach, A., Bai, J., Jackson, M.B., Chapman, E.R. and Morton, A.J. ( 2003 ) Expression of mutant huntingtin blocks exocytosis in PC12 cells by depletion of complexin II. J. Biol. Chem. , 278 , 30849 –30853. (10.1074/jbc.M304615200)
  48. Hansson, O., Petersén, Å., Leist, M., Nicotera, P., Castilho, R.F. and Brundin, P. ( 1999 ) Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. Proc. Natl Acad. Sci. USA , 96 , 8727 –8732. (10.1073/pnas.96.15.8727)
  49. Hohmeier, H.E., Mulder, H., Chen, G., Henkel-Rieger, R., Prentki, M. and Newgard, C.B. ( 2000 ) Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes , 49 , 424 –430. (10.2337/diabetes.49.3.424)
  50. Mulder, H., Lindh, A.C. and Sundler, F. ( 1993 ) Islet amyloid polypeptide gene expression in the endocrine pancreas of the rat: a combined in situ hybridization and immunocytochemical study. Cell Tissue Res. , 274 , 467 –474. (10.1007/BF00314543)
  51. Barg, S., Galvanovskis, J., Göpel, S.O., Rorsman, P. and Eliasson, L. ( 2000 ) Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. Diabetes , 49 , 1500 –1510. (10.2337/diabetes.49.9.1500)
Dates
Type When
Created 20 years, 7 months ago (Jan. 13, 2005, 8:18 p.m.)
Deposited 5 years, 4 months ago (April 5, 2020, 5:30 a.m.)
Indexed 11 months, 4 weeks ago (Sept. 6, 2024, 3:41 p.m.)
Issued 20 years, 7 months ago (Jan. 13, 2005)
Published 20 years, 7 months ago (Jan. 13, 2005)
Published Online 20 years, 7 months ago (Jan. 13, 2005)
Published Print 20 years, 6 months ago (March 1, 2005)
Funders 0

None

@article{Bj_rkqvist_2005, title={The R6/2 transgenic mouse model of Huntington’s disease develops diabetes due to deficient β-cell mass and exocytosis}, volume={14}, ISSN={0964-6906}, url={http://dx.doi.org/10.1093/hmg/ddi053}, DOI={10.1093/hmg/ddi053}, number={5}, journal={Human Molecular Genetics}, publisher={Oxford University Press (OUP)}, author={Björkqvist, Maria and Fex, Malin and Renström, Erik and Wierup, Nils and Petersén, Åsa and Gil, Joana and Bacos, Karl and Popovic, Natalija and Li, Jia-Yi and Sundler, Frank and Brundin, Patrik and Mulder, Hindrik}, year={2005}, month=jan, pages={565–574} }