Human Molecular Genetics, Vol 7, 783-790, Copyright © 1998 by Oxford University Press
JK Cooper, G Schilling, MF Peters, WJ Herring, AH Sharp, Z Kaminsky, J Masone, FA Khan, M Delanoy, DR Borchelt, VL Dawson, TM Dawson and CA Ross
Huntington's disease (HD) is a progressive neurodegenerative disorder
caused by an expanding CAG repeat coding for polyglutamine in the
huntingtin protein. Recent data have suggested the possibility that an
N-terminal fragment of huntingtin may aggregate in neurons of patients with
HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus,
forming intranuclear neuronal inclusion bodies. An animal model of HD using
the short N-terminal fragment of huntingtin has also been found to have
intranuclear inclusions and this same fragment can aggregate in vitro . We
have now developed a cell culture model demonstrating that N-terminal
fragments of huntingtin with expanded glutamine repeats aggregate both in
the cytoplasm and in the nucleus. Neuroblastoma cells transiently
transfected with full-length huntingtin constructs with either a normal or
expanded repeat had diffuse cytoplasmic localization of the protein. In
contrast, cells transfected with truncated N-terminal fragments showed
aggregation only if the glutamine repeat was expanded. The aggregates were
often ubiquitinated. The shorter truncated product appeared to form more
aggregates in the nucleus. Cells transfected with the expanded repeat
construct but not the normal repeat construct showed enhanced toxicity to
the apoptosis- inducing agent staurosporine. These data indicate that
N-terminal truncated fragments of huntingtin with expanded glutamine
repeats can aggregate in cells in culture and that this aggregation can be
toxic to cells. This model will be useful for future experiments to test
mechanisms of aggregation and toxicity and potentially for testing
experimental therapeutic interventions.
ARTICLES
Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. B. Brown, A. I. Bogush, and M. E. Ehrlich Neocortical expression of mutant huntingtin is not required for alterations in striatal gene expression or motor dysfunction in a transgenic mouse Hum. Mol. Genet., October 15, 2008; 17(20): 3095 - 3104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Bichelmeier, T. Schmidt, J. Hubener, J. Boy, L. Ruttiger, K. Habig, S. Poths, M. Bonin, M. Knipper, W. J. Schmidt, et al. Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3: In Vivo Evidence J. Neurosci., July 11, 2007; 27(28): 7418 - 7428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fukui and C. T. Moraes Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates Hum. Mol. Genet., April 1, 2007; 16(7): 783 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Li, H.-H. Wang, S.-J. Liu, Y.-Q. Deng, Y.-J. Zhang, Q. Tian, X.-C. Wang, X.-Q. Chen, Y. Yang, J.-Y. Zhang, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration PNAS, February 27, 2007; 104(9): 3591 - 3596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Marchut and C. K. Hall Side-Chain Interactions Determine Amyloid Formation by Model Polyglutamine Peptides in Molecular Dynamics Simulations Biophys. J., June 15, 2006; 90(12): 4574 - 4584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Underwood, D. Broadhurst, W. B. Dunn, D. I. Ellis, A. W. Michell, C. Vacher, D. E. Mosedale, D. B. Kell, R. A. Barker, D. J. Grainger, et al. Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles Brain, April 1, 2006; 129(4): 877 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Mukai, T. Isagawa, E. Goyama, S. Tanaka, N. F. Bence, A. Tamura, Y. Ono, and R. R. Kopito Formation of morphologically similar globular aggregates from diverse aggregation-prone proteins in mammalian cells PNAS, August 2, 2005; 102(31): 10887 - 10892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Poirier, H. Jiang, and C. A. Ross A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure Hum. Mol. Genet., March 15, 2005; 14(6): 765 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Everett and N. W. Wood Trinucleotide repeats and neurodegenerative disease Brain, November 1, 2004; 127(11): 2385 - 2405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Rousseau, B. Dehay, L. Ben-Haiem, Y. Trottier, M. Morange, and A. Bertolotti Targeting expression of expanded polyglutamine proteins to the endoplasmic reticulum or mitochondria prevents their aggregation PNAS, June 29, 2004; 101(26): 9648 - 9653. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Tsai, H.-Y. Kao, A. Mitzutani, E. Banayo, H. Rajan, M. McKeown, and R. M. Evans Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors PNAS, March 23, 2004; 101(12): 4047 - 4052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Cookson, P. J. Lockhart, C. McLendon, C. O'Farrell, M. Schlossmacher, and M. J. Farrer RING finger 1 mutations in Parkin produce altered localization of the protein Hum. Mol. Genet., November 15, 2003; 12(22): 2957 - 2965. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhou, F. Cao, Z. Wang, Z.-X. Yu, H.-P. Nguyen, J. Evans, S.-H. Li, and X.-J. Li Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity J. Cell Biol., October 13, 2003; 163(1): 109 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Jackson, S. J. Tallaksen-Greene, R. L. Albin, and P. J. Detloff Nucleocytoplasmic transport signals affect the age at onset of abnormalities in knock-in mice expressing polyglutamine within an ectopic protein context Hum. Mol. Genet., July 1, 2003; 12(13): 1621 - 1629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xia, D. H. Lee, J. Taylor, M. Vandelft, and R. Truant Huntingtin contains a highly conserved nuclear export signal Hum. Mol. Genet., June 15, 2003; 12(12): 1393 - 1403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. C. Nucifora Jr., L. M. Ellerby, C. L. Wellington, J. D. Wood, W. J. Herring, A. Sawa, M. R. Hayden, V. L. Dawson, T. M. Dawson, and C. A. Ross Nuclear Localization of a Non-caspase Truncation Product of Atrophin-1, with an Expanded Polyglutamine Repeat, Increases Cellular Toxicity J. Biol. Chem., April 4, 2003; 278(15): 13047 - 13055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jiang, F. C. Nucifora Jr, C. A. Ross, and D. B. DeFranco Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein Hum. Mol. Genet., January 1, 2003; 12(1): 1 - 12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-L. Wu, T. M. O'Kane, R. W. Scott, M. J. Savage, and D. Bozyczko-Coyne Protein Tyrosine Phosphatases Are Up-regulated and Participate in Cell Death Induced by Polyglutamine Expansion J. Biol. Chem., November 8, 2002; 277(46): 44208 - 44213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kita, J. Carmichael, J. Swartz, S. Muro, A. Wyttenbach, K. Matsubara, D. C. Rubinsztein, and K. Kato Modulation of polyglutamine-induced cell death by genes identified by expression profiling Hum. Mol. Genet., September 15, 2002; 11(19): 2279 - 2287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Wellington, L. M. Ellerby, C.-A. Gutekunst, D. Rogers, S. Warby, R. K. Graham, O. Loubser, J. van Raamsdonk, R. Singaraja, Y.-Z. Yang, et al. Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease J. Neurosci., September 15, 2002; 22(18): 7862 - 7872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Milewski, J. E. Mickle, J. K. Forrest, B. A. Stanton, and G. R. Cutting Aggregation of Misfolded Proteins Can Be a Selective Process Dependent upon Peptide Composition J. Biol. Chem., September 6, 2002; 277(37): 34462 - 34470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Dunah, H. Jeong, A. Griffin, Y.-M. Kim, D. G. Standaert, S. M. Hersch, M. M. Mouradian, A. B. Young, N. Tanese, and D. Krainc Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease Science, June 21, 2002; 296(5576): 2238 - 2243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. de Almeida, C. A. Ross, D. Zala, P. Aebischer, and N. Deglon Lentiviral-Mediated Delivery of Mutant Huntingtin in the Striatum of Rats Induces a Selective Neuropathology Modulated by Polyglutamine Repeat Size, Huntingtin Expression Levels, and Protein Length J. Neurosci., May 1, 2002; 22(9): 3473 - 3483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Lovestone and D M McLoughlin Protein aggregates and dementia: is there a common toxicity? J. Neurol. Neurosurg. Psychiatry, February 1, 2002; 72(2): 152 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khoshnan, J. Ko, and P. H. Patterson Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity PNAS, January 22, 2002; 99(2): 1002 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhou, S.-H. Li, and X.-J. Li Chaperone Suppression of Cellular Toxicity of Huntingtin Is Independent of Polyglutamine Aggregation J. Biol. Chem., December 14, 2001; 276(51): 48417 - 48424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Rajan, M. E. Illing, N. F. Bence, and R. R. Kopito Specificity in intracellular protein aggregation and inclusion body formation PNAS, October 25, 2001; (2001) 181479798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Hughes, R. S. Lo, C. Davis, A. D. Strand, C. L. Neal, J. M. Olson, and S. Fields Altered transcription in yeast expressing expanded polyglutamine PNAS, October 25, 2001; (2001) 191498198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wyttenbach, J. Swartz, H. Kita, T. Thykjaer, J. Carmichael, J. Bradley, R. Brown, M. Maxwell, A. Schapira, T. F. Orntoft, et al. Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease Hum. Mol. Genet., August 1, 2001; 10(17): 1829 - 1845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Petersen, K. E. Larsen, G. G. Behr, N. Romero, S. Przedborski, P. Brundin, and D. Sulzer Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration Hum. Mol. Genet., June 1, 2001; 10(12): 1243 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Waelter, A. Boeddrich, R. Lurz, E. Scherzinger, G. Lueder, H. Lehrach, and E. E. Wanker Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation Mol. Biol. Cell, May 1, 2001; 12(5): 1393 - 1407. [Abstract] [Full Text]
|
|
|
|
|
|
W. Chun, M. Lesort, J. Tucholski, C. A. Ross, and G. V.W. Johnson Tissue Transglutaminase Does Not Contribute to the Formation of Mutant Huntingtin Aggregates J. Cell Biol., March 26, 2001; 153(1): 25 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Nucifora Jr., M. Sasaki, M. F. Peters, H. Huang, J. K. Cooper, M. Yamada, H. Takahashi, S. Tsuji, J. Troncoso, V. L. Dawson, et al. Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity Science, March 23, 2001; 291(5512): 2423 - 2428. [Abstract] [Full Text]
|
|
|
|
|
|
G. Cancel, C. Duyckaerts, M. Holmberg, C. Zander, G. Yvert, A.-S. Lebre, M. Ruberg, B. Faucheux, Y. Agid, E. Hirsch, et al. Distribution of ataxin-7 in normal human brain and retina Brain, December 1, 2000; 123(12): 2519 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Jana, M. Tanaka, G.-h. Wang, and N. Nukina Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity Hum. Mol. Genet., August 12, 2000; 9(13): 2009 - 2018. [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]
|
|
|
|
|
|
R. Luthi-Carter, A. Strand, N. L. Peters, S. M. Solano, Z. R. Hollingsworth, A. S. Menon, A. S. Frey, B. S. Spektor, E. B. Penney, G. Schilling, et al. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease Hum. Mol. Genet., May 22, 2000; 9(9): 1259 - 1271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Shibata, D. P. Huynh, and S.-M. Pulst A novel protein with RNA-binding motifs interacts with ataxin-2 Hum. Mol. Genet., May 22, 2000; 9(9): 1303 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Rigamonti, J. H. Bauer, C. De-Fraja, L. Conti, S. Sipione, C. Sciorati, E. Clementi, A. Hackam, M. R. Hayden, Y. Li, et al. Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3 J. Neurosci., May 15, 2000; 20(10): 3705 - 3713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wyttenbach, J. Carmichael, J. Swartz, R. A. Furlong, Y. Narain, J. Rankin, and D. C. Rubinsztein Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease PNAS, March 14, 2000; 97(6): 2898 - 2903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yoshizawa, Y. Yamagishi, N. Koseki, J. Goto, H. Yoshida, F. Shibasaki, S.'i. Shoji, and I. Kanazawa Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch Hum. Mol. Genet., January 1, 2000; 9(1): 69 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Simeoni, M. A. Mancini, D. L. Stenoien, M. Marcelli, N. L. Weigel, M. Zanisi, L. Martini, and A. Poletti Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract Hum. Mol. Genet., January 1, 2000; 9(1): 133 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chai, S. L. Koppenhafer, N. M. Bonini, and H. L. Paulson Analysis of the Role of Heat Shock Protein (Hsp) Molecular Chaperones in Polyglutamine Disease J. Neurosci., December 1, 1999; 19(23): 10338 - 10347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Narain, A. Wyttenbach, J. Rankin, R. A Furlong, and D. C Rubinsztein A molecular investigation of true dominance in Huntington's disease J. Med. Genet., October 1, 1999; 36(10): 739 - 746. [Abstract] [Full Text]
|
|
|
|
|
|
A. Kazantsev, E. Preisinger, A. Dranovsky, D. Goldgaber, and D. Housman Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells PNAS, September 28, 1999; 96(20): 11404 - 11409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Li, A. L. Cheng, H. Li, and X.-J. Li Cellular Defects and Altered Gene Expression in PC12 Cells Stably Expressing Mutant Huntingtin J. Neurosci., July 1, 1999; 19(13): 5159 - 5172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-A. Gutekunst, S.-H. Li, H. Yi, J. S. Mulroy, S. Kuemmerle, R. Jones, D. Rye, R. J. Ferrante, S. M. Hersch, and X.-J. Li Nuclear and Neuropil Aggregates in Huntington's Disease: Relationship to Neuropathology J. Neurosci., April 1, 1999; 19(7): 2522 - 2534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D C Rubinsztein, A Wyttenbach, and J Rankin Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts? J. Med. Genet., April 1, 1999; 36(4): 265 - 270. [Abstract] [Full Text]
|
|
|
|
|
|
L. M. Ellerby, R. L. Andrusiak, C. L. Wellington, A. S. Hackam, S. S. Propp, J. D. Wood, A. H. Sharp, R. L. Margolis, C. A. Ross, G. S. Salvesen, et al. Cleavage of Atrophin-1 at Caspase Site Aspartic Acid 109 Modulates Cytotoxicity J. Biol. Chem., March 26, 1999; 274(13): 8730 - 8736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kim, H-S Lee, G. LaForet, C. McIntyre, E. J. Martin, P. Chang, T. W. Kim, M. Williams, P. H. Reddy, D. Tagle, et al. Mutant Huntingtin Expression in Clonal Striatal Cells: Dissociation of Inclusion Formation and Neuronal Survival by Caspase Inhibition J. Neurosci., February 1, 1999; 19(3): 964 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Faber, J. R. Alter, M. E. MacDonald, and A. C. Hart Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron PNAS, January 5, 1999; 96(1): 179 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Perez, H. L. Paulson, S. J. Pendse, S. J. Saionz, N. M. Bonini, and R. N. Pittman Recruitment and the Role of Nuclear Localization in Polyglutamine-mediated Aggregation J. Cell Biol., December 14, 1998; 143(6): 1457 - 1470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Hackam, R. Singaraja, C. L. Wellington, M. Metzler, K. McCutcheon, T. Zhang, M. Kalchman, and M. R. Hayden The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity J. Cell Biol., June 1, 1998; 141(5): 1097 - 1105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Miller, H. Rauer, H. Tomita, H. Rauer, J. J. Gargus, G. A. Gutman, M. D. Cahalan, and K. G. Chandy Nuclear Localization and Dominant-negative Suppression by a Mutant SKCa3 N-terminal Channel Fragment Identified in a Patient with Schizophrenia J. Biol. Chem., July 20, 2001; 276(30): 27753 - 27756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Wellington, R. Singaraja, L. Ellerby, J. Savill, S. Roy, B. Leavitt, E. Cattaneo, A. Hackam, A. Sharp, N. Thornberry, et al. Inhibiting Caspase Cleavage of Huntingtin Reduces Toxicity and Aggregate Formation in Neuronal and Nonneuronal Cells J. Biol. Chem., June 23, 2000; 275(26): 19831 - 19838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khoshnan, J. Ko, and P. H. Patterson Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity PNAS, January 22, 2002; 99(2): 1002 - 1007. [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]
|
|
|
|
|
|