Human Molecular Genetics, Vol 8, 813-822, Copyright © 1999 by Oxford University Press
K Sathasivam, C Hobbs, M Turmaine, L Mangiarini, A Mahal, F Bertaux, EE Wanker, P Doherty, SW Davies and GP Bates
Huntington's disease (HD) is one of a class of inherited progressive
neurodegenerative disorders that are caused by a CAG/polyglutamine repeat
expansion. We have previously generated mice that are transgenic for exon 1
of the HD gene carrying highly expanded CAG repeats which develop a
progressive movement disorder and weight loss with similarities to HD.
Neuronal inclusions composed of the exon 1 protein and ubiquitin are
present in specific brain regions prior to onset of the phenotype, which in
turn occurs long before specific neurodegeneration can be detected. In this
report we have extended the search for polyglutamine inclusions to
non-neuronal tissues. Outside the central nervous system (CNS), inclusions
were identified in a variety of post-mitotic cells. This is consistent with
a concentration- dependent nucleation and aggregation model of inclusion
formation and indicates that brain-specific factors are not necessary for
this process. To possibly gain insights into the wasting that is observed
in the human disease, we have conducted a detailed analysis of the timing
and progression of inclusion formation in skeletal muscle and an
investigation into the cause of the severe muscle atrophy that occurs in
the mouse model. The formation of inclusions in non-CNS tissues will be
particularly useful with respect to in vivo monitoring of pharmaceutical
agents selected for their ability to prevent polyglutamine aggregation in
vitro, without the requirement that the agent can cross the blood-brain
barrier in the first instance.
ARTICLES
Formation of polyglutamine inclusions in non-CNS tissue
Medical and Molecular Genetics, GKT Medical and Dental School, King's College, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M.-C. Chiang, H.-M. Chen, H.-L. Lai, H.-W. Chen, S.-Y. Chou, C.-M. Chen, F.-J. Tsai, and Y. Chern The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system Hum. Mol. Genet., August 15, 2009; 18(16): 2929 - 2942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Chaturvedi, P. Adhihetty, S. Shukla, T. Hennessy, N. Calingasan, L. Yang, A. Starkov, M. Kiaei, M. Cannella, J. Sassone, et al. Impaired PGC-1{alpha} function in muscle in Huntington's disease Hum. Mol. Genet., August 15, 2009; 18(16): 3048 - 3065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Martin, E. Golden, O. D. Carlson, P. Pistell, J. Zhou, W. Kim, B. P. Frank, S. Thomas, W. A. Chadwick, N. H. Greig, et al. Exendin-4 Improves Glycemic Control, Ameliorates Brain and Pancreatic Pathologies, and Extends Survival in a Mouse Model of Huntington's Disease Diabetes, February 1, 2009; 58(2): 318 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bjorkqvist, E. J. Wild, J. Thiele, A. Silvestroni, R. Andre, N. Lahiri, E. Raibon, R. V. Lee, C. L. Benn, D. Soulet, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease J. Exp. Med., August 4, 2008; 205(8): 1869 - 1877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Lalic, J. Maric, M. Svetel, A. Jotic, E. Stefanova, K. Lalic, N. Dragasevic, T. Milicic, L. Lukic, and V. S. Kostic Glucose Homeostasis in Huntington Disease: Abnormalities in Insulin Sensitivity and Early-Phase Insulin Secretion Arch Neurol, April 1, 2008; 65(4): 476 - 480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vidal, L. Miravalle, X. Gao, A. G. Barbeito, M. A. Baraibar, S. K. Hekmatyar, M. Widel, N. Bansal, M. B. Delisle, and B. Ghetti Expression of a Mutant Form of the Ferritin Light Chain Gene Induces Neurodegeneration and Iron Overload in Transgenic Mice J. Neurosci., January 2, 2008; 28(1): 60 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Latouche, C. Lasbleiz, E. Martin, V. Monnier, T. Debeir, A. Mouatt-Prigent, M.-P. Muriel, L. Morel, M. Ruberg, A. Brice, et al. A Conditional Pan-Neuronal Drosophila Model of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes J. Neurosci., March 7, 2007; 27(10): 2483 - 2492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Chiang, H.-M. Chen, Y.-H. Lee, H.-H. Chang, Y.-C. Wu, B.-W. Soong, C.-M. Chen, Y.-R. Wu, C.-S. Liu, D.-M. Niu, et al. Dysregulation of C/EBP{alpha} by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease Hum. Mol. Genet., March 1, 2007; 16(5): 483 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bjorkqvist, A. Petersen, K. Bacos, J. Isaacs, P. Norlen, J. Gil, N. Popovic, F. Sundler, G. P. Bates, S. J. Tabrizi, et al. Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease Hum. Mol. Genet., May 15, 2006; 15(10): 1713 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Berger, J. E. Davies, S. Luo, M. Y. Pasco, I. Majoul, C. J. O'Kane, and D. C. Rubinsztein Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion Hum. Mol. Genet., February 1, 2006; 15(3): 453 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fujimoto, E. Takaki, T. Hayashi, Y. Kitaura, Y. Tanaka, S. Inouye, and A. Nakai Active HSF1 Significantly Suppresses Polyglutamine Aggregate Formation in Cellular and Mouse Models J. Biol. Chem., October 14, 2005; 280(41): 34908 - 34916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Strand, A. K. Aragaki, D. Shaw, T. Bird, J. Holton, C. Turner, S. J. Tapscott, S. J. Tabrizi, A. H. Schapira, C. Kooperberg, et al. Gene expression in Huntington's disease skeletal muscle: a potential biomarker Hum. Mol. Genet., July 1, 2005; 14(13): 1863 - 1876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bjorkqvist, M. Fex, E. Renstrom, N. Wierup, A. Petersen, J. Gil, K. Bacos, N. Popovic, J.-Y. Li, F. Sundler, et al. The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient {beta}-cell mass and exocytosis Hum. Mol. Genet., March 1, 2005; 14(5): 565 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Colton, Q. Xu, J. R. Burke, S. Y. Bae, J. K. Wakefield, A. Nair, W. J. Strittmatter, and M. P. Vitek Disrupted Spermine Homeostasis: A Novel Mechanism in Polyglutamine-Mediated Aggregation and Cell Death J. Neurosci., August 11, 2004; 24(32): 7118 - 7127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Helmlinger, G. Abou-Sleymane, G. Yvert, S. Rousseau, C. Weber, Y. Trottier, J.-L. Mandel, and D. Devys Disease Progression Despite Early Loss of Polyglutamine Protein Expression in SCA7 Mouse Model J. Neurosci., February 25, 2004; 24(8): 1881 - 1887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Helmlinger, G. Yvert, S. Picaud, K. Merienne, J. Sahel, J.-L. Mandel, and D. Devys Progressive retinal degeneration and dysfunction in R6 Huntington's disease mice Hum. Mol. Genet., December 15, 2002; 11(26): 3351 - 3359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Djousse, B. Knowlton, L. A. Cupples, K. Marder, I. Shoulson, and R. H. Myers Weight loss in early stage of Huntington's disease Neurology, November 12, 2002; 59(9): 1325 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Luthi-Carter, S. A. Hanson, A. D. Strand, D. A. Bergstrom, W. Chun, N. L. Peters, A. M. Woods, E. Y. Chan, C. Kooperberg, D. Krainc, et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain Hum. Mol. Genet., August 15, 2002; 11(17): 1911 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zabel, D. C. Chamrad, J. Priller, B. Woodman, H. E. Meyer, G. P. Bates, and J. Klose Alterations in the Mouse and Human Proteome Caused by Huntington's Disease Mol. Cell. Proteomics, May 1, 2002; 1(5): 366 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sathasivam, B. Woodman, A. Mahal, F. Bertaux, E. E. Wanker, D. T. Shima, and G. P. Bates Centrosome disorganization in fibroblast cultures derived from R6/2 Huntington's disease (HD) transgenic mice and HD patients Hum. Mol. Genet., October 1, 2001; 10(21): 2425 - 2435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Adachi, A. Kume, M. Li, Y. Nakagomi, H. Niwa, J. Do, C. Sang, Y. Kobayashi, M. Doyu, and G. Sobue Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death Hum. Mol. Genet., May 1, 2001; 10(10): 1039 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Carmichael, J. Chatellier, A. Woolfson, C. Milstein, A. R. Fersht, and D. C. Rubinsztein Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease PNAS, July 30, 2000; (2000) 170280697. [Abstract] [Full Text]
|
|
|
|
|
|
C. J. Cummings and H. Y. Zoghbi Fourteen and counting: unraveling trinucleotide repeat diseases Hum. Mol. Genet., April 1, 2000; 9(6): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Kaytor and S. T. Warren Aberrant Protein Deposition and Neurological Disease J. Biol. Chem., December 31, 1999; 274(53): 37507 - 37510. [Full Text] [PDF]
|
|
|
|
|
|
H. Li, S.-H. Li, A. L. Cheng, L. Mangiarini, G. P. Bates, and X.-J. Li Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice Hum. Mol. Genet., July 1, 1999; 8(7): 1227 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Muchowski, K. Ning, C. D'Souza-Schorey, and S. Fields Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment PNAS, January 22, 2002; 99(2): 727 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Carmichael, J. Chatellier, A. Woolfson, C. Milstein, A. R. Fersht, and D. C. Rubinsztein Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease PNAS, August 15, 2000; 97(17): 9701 - 9705. [Abstract] [Full Text] [PDF]
|
|