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Science 26 September 1997:
Vol. 277. no. 5334, pp. 1990 - 1993
DOI: 10.1126/science.277.5334.1990
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Reports

Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain

Marian DiFiglia, * Ellen Sapp, Kathryn O. Chase, Stephen W. Davies, Gillian P. Bates, J. P. Vonsattel, Neil Aronin

The cause of neurodegeneration in Huntington's disease (HD) is unknown. Patients with HD have an expanded NH2-terminal polyglutamine region in huntingtin. An NH2-terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs) in the HD cortex and striatum, which are affected in HD, and polyglutamine length influenced the extent of huntingtin accumulation in these structures. Ubiquitin was also found in NIIs and DNs, which suggests that abnormal huntingtin is targeted for proteolysis but is resistant to removal. The aggregation of mutant huntingtin may be part of the pathogenic mechanism in HD.

M. DiFiglia, E. Sapp, J. P. Vonsattel, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
S. W. Davies, Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E, 6BT, UK.
G. P. Bates, Division of Medical and Molecular Genetics, UMDS Guy's Hospital, London SE1 7E H, UK.
K. O. Chase, N. Aronin, Departments of Medicine and Cell Biology, University of Massachusetts Medical Center, Worcester, MA 01655, USA.
*   To whom correspondence should be addressed.

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J. Biol. Chem. 284, 1917-1929
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H. Runne, E. Regulier, A. Kuhn, D. Zala, O. Gokce, V. Perrin, B. Sick, P. Aebischer, N. Deglon, and R. Luthi-Carter (2008)
J. Neurosci. 28, 9723-9731
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Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease.
C.-E. Wang, S. Tydlacka, A. L. Orr, S.-H. Yang, R. K. Graham, M. R. Hayden, S. Li, A. W.S. Chan, and X.-J. Li (2008)
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Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease.
S. Metzger, J. Rong, H.-P. Nguyen, A. Cape, J. Tomiuk, A. S. Soehn, P. Propping, Y. Freudenberg-Hua, J. Freudenberg, L. Tong, et al. (2008)
Hum. Mol. Genet. 17, 1137-1146
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Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice.
J. Wang, C.-E. Wang, A. Orr, S. Tydlacka, S.-H. Li, and X.-J. Li (2008)
J. Cell Biol. 180, 1177-1189
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Histone Deacetylase Inhibition Modulates Kynurenine Pathway Activation in Yeast, Microglia, and Mice Expressing a Mutant Huntingtin Fragment.
F. Giorgini, T. Moller, W. Kwan, D. Zwilling, J. L. Wacker, S. Hong, L.-C. L. Tsai, C. S. Cheah, R. Schwarcz, P. Guidetti, et al. (2008)
J. Biol. Chem. 283, 7390-7400
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N-Terminal Mutant Huntingtin Associates with Mitochondria and Impairs Mitochondrial Trafficking.
A. L. Orr, S. Li, C.-E. Wang, H. Li, J. Wang, J. Rong, X. Xu, P. G. Mastroberardino, J. T. Greenamyre, and X.-J. Li (2008)
J. Neurosci. 28, 2783-2792
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Noninvasive Measurement of Protein Aggregation by Mutant Huntingtin Fragments or {alpha}-Synuclein in the Lens.
P. J. Muchowski, R. Ramsden, Q. Nguyen, E. E. Arnett, T. M. Greiling, S. K. Anderson, and J. I. Clark (2008)
J. Biol. Chem. 283, 6330-6336
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Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic.
T. Takahashi, S. Kikuchi, S. Katada, Y. Nagai, M. Nishizawa, and O. Onodera (2008)
Hum. Mol. Genet. 17, 345-356
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Protein Misfolding and Neurodegeneration.
C. Soto and L. D. Estrada (2008)
Arch Neurol 65, 184-189
   Abstract »    Full Text »    PDF »
Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity.
R. S. Atwal, J. Xia, D. Pinchev, J. Taylor, R. M. Epand, and R. Truant (2007)
Hum. Mol. Genet. 16, 2600-2615
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Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits.
M. DiFiglia, M. Sena-Esteves, K. Chase, E. Sapp, E. Pfister, M. Sass, J. Yoder, P. Reeves, R. K. Pandey, K. G. Rajeev, et al. (2007)
PNAS 104, 17204-17209
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A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse.
V. Chopra, J. H. Fox, G. Lieberman, K. Dorsey, W. Matson, P. Waldmeier, D. E. Housman, A. Kazantsev, A. B. Young, and S. Hersch (2007)
PNAS 104, 16685-16689
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Polyglutamine diseases: emerging concepts in pathogenesis and therapy.
J. Shao and M. I. Diamond (2007)
Hum. Mol. Genet. 16, R115-R123
   Abstract »    Full Text »    PDF »
Proteolytic Cleavage of Ataxin-7 by Caspase-7 Modulates Cellular Toxicity and Transcriptional Dysregulation.
J. E. Young, L. Gouw, S. Propp, B. L. Sopher, J. Taylor, A. Lin, E. Hermel, A. Logvinova, S. F. Chen, S. Chen, et al. (2007)
J. Biol. Chem. 282, 30150-30160
   Abstract »    Full Text »    PDF »
Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation.
M. Valenza, J. B. Carroll, V. Leoni, L. N. Bertram, I. Bjorkhem, R. R. Singaraja, S. Di Donato, D. Lutjohann, M. R. Hayden, and E. Cattaneo (2007)
Hum. Mol. Genet. 16, 2187-2198
   Abstract »    Full Text »    PDF »
Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3: In Vivo Evidence.
U. Bichelmeier, T. Schmidt, J. Hubener, J. Boy, L. Ruttiger, K. Habig, S. Poths, M. Bonin, M. Knipper, W. J. Schmidt, et al. (2007)
J. Neurosci. 27, 7418-7428
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Calpain Inhibition Is Sufficient to Suppress Aggregation of Polyglutamine-expanded Ataxin-3.
A. Haacke, F. U. Hartl, and P. Breuer (2007)
J. Biol. Chem. 282, 18851-18856
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Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation.
A. Zourlidou, T. Gidalevitz, M. Kristiansen, C. Landles, B. Woodman, D. J. Wells, D. S. Latchman, J. de Belleroche, S. J. Tabrizi, R. I. Morimoto, et al. (2007)
Hum. Mol. Genet. 16, 1078-1090
   Abstract »    Full Text »    PDF »
Systematic Uncovering of Multiple Pathways Underlying the Pathology of Huntington Disease by an Acid-cleavable Isotope-coded Affinity Tag Approach.
M.-C. Chiang, C.-G. Juo, H.-H. Chang, H.-M. Chen, E. C. Yi, and Y. Chern (2007)
Mol. Cell. Proteomics 6, 781-797
   Abstract »    Full Text »    PDF »
The Mrj co-chaperone mediates keratin turnover and prevents the formation of toxic inclusion bodies in trophoblast cells of the placenta.
E. D. Watson, C. Geary-Joo, M. Hughes, and J. C. Cross (2007)
Development 134, 1809-1817
   Abstract »    Full Text »    PDF »
Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates.
H. Fukui and C. T. Moraes (2007)
Hum. Mol. Genet. 16, 783-797
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CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease.
J. Jung and N. Bonini (2007)
Science 315, 1857-1859
   Abstract »    Full Text »    PDF »
Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model.
N. W. Schiffer, S. A. Broadley, T. Hirschberger, P. Tavan, H. A. Kretzschmar, A. Giese, C. Haass, F. U. Hartl, and B. Schmid (2007)
J. Biol. Chem. 282, 9195-9203
   Abstract »    Full Text »    PDF »
Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and {alpha}-Synuclein.
S. Sarkar, J. E. Davies, Z. Huang, A. Tunnacliffe, and D. C. Rubinsztein (2007)
J. Biol. Chem. 282, 5641-5652
   Abstract »    Full Text »    PDF »
The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis.
E. Rockabrand, N. Slepko, A. Pantalone, V. N. Nukala, A. Kazantsev, J. L. Marsh, P. G. Sullivan, J. S. Steffan, S. L. Sensi, and L. M. Thompson (2007)
Hum. Mol. Genet. 16, 61-77
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Dopamine enhances motor and neuropathological consequences of polyglutamine expanded huntingtin.
M. Cyr, T. D. Sotnikova, R. R. Gainetdinov, and M. G. Caron (2006)
FASEB J 20, 2541-2543
   Abstract »    Full Text »    PDF »
Critical Role of the Proline-rich Region in Huntingtin for Aggregation and Cytotoxicity in Yeast.
B. Dehay and A. Bertolotti (2006)
J. Biol. Chem. 281, 35608-35615
   Abstract »    Full Text »    PDF »
Context-dependent Dysregulation of Transcription by Mutant Huntingtin.
J. Cornett, L. Smith, M. Friedman, J.-Y. Shin, X.-J. Li, and S.-H. Li (2006)
J. Biol. Chem. 281, 36198-36204
   Abstract »    Full Text »    PDF »
Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease.
H. P. Nguyen, P. Kobbe, H. Rahne, T. Worpel, B. Jager, M. Stephan, R. Pabst, C. Holzmann, O. Riess, H. Korr, et al. (2006)
Hum. Mol. Genet. 15, 3177-3194
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Cholinergic neuronal defect without cell loss in Huntington's disease.
R. Smith, H. Chung, S. Rundquist, M. L.C. Maat-Schieman, L. Colgan, E. Englund, Y.-J. Liu, R. A.C. Roos, R. L.M. Faull, P. Brundin, et al. (2006)
Hum. Mol. Genet. 15, 3119-3131
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Polyalanine and polyserine frameshift products in Huntington's disease.
J E Davies and D C Rubinsztein (2006)
J. Med. Genet. 43, 893-896
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Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III.
A. Solans, A. Zambrano, M. Rodriguez, and A. Barrientos (2006)
Hum. Mol. Genet. 15, 3063-3081
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Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of huntington's disease.
D. M. Cummings, A. J. Milnerwood, G. M. Dallerac, V. Waights, J. Y. Brown, S. C. Vatsavayai, M. C. Hirst, and K. P.S.J. Murphy (2006)
Hum. Mol. Genet. 15, 2856-2868
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Transgenic expression of {beta}-APP in fast-twitch skeletal muscle leads to calcium dyshomeostasis and IBM-like pathology.
C. E-H. Moussa, Q. Fu, P. Kumar, A. Shtifman, J. R. Lopez, P. D. Allen, F. LaFerla, D. Weinberg, J. Magrane, T. Aprahamian, et al. (2006)
FASEB J 20, 2165-2167
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Normal-repeat-length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins.
N. Slepko, A. M. Bhattacharyya, G. R. Jackson, J. S. Steffan, J. L. Marsh, L. M. Thompson, and R. Wetzel (2006)
PNAS 103, 14367-14372
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Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models.
D. E. Ehrnhoefer, M. Duennwald, P. Markovic, J. L. Wacker, S. Engemann, M. Roark, J. Legleiter, J. L. Marsh, L. M. Thompson, S. Lindquist, et al. (2006)
Hum. Mol. Genet. 15, 2743-2751
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Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model..
H. R. Brignull, F. E. Moore, S. J. Tang, and R. I. Morimoto (2006)
J. Neurosci. 26, 7597-7606
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Flanking sequences profoundly alter polyglutamine toxicity in yeast.
M. L. Duennwald, S. Jagadish, P. J. Muchowski, and S. Lindquist (2006)
PNAS 103, 11045-11050
   Abstract »    Full Text »    PDF »
The Two-stage Pathway of Ataxin-3 Fibrillogenesis Involves a Polyglutamine-independent Step.
A. M. Ellisdon, B. Thomas, and S. P. Bottomley (2006)
J. Biol. Chem. 281, 16888-16896
   Abstract »    Full Text »    PDF »
Expression and Characterization of Full-length Human Huntingtin, an Elongated HEAT Repeat Protein.
W. Li, L. C. Serpell, W. J. Carter, D. C. Rubinsztein, and J. A. Huntington (2006)
J. Biol. Chem. 281, 15916-15922
   Abstract »    Full Text »    PDF »
Regulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1.
M. Shibata, T. Lu, T. Furuya, A. Degterev, N. Mizushima, T. Yoshimori, M. MacDonald, B. Yankner, and J. Yuan (2006)
J. Biol. Chem. 281, 14474-14485
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Early development of aberrant synaptic plasticity in a mouse model of Huntington's disease.
A. J. Milnerwood, D. M. Cummings, G. M. Dallerac, J. Y. Brown, S. C. Vatsavayai, M. C. Hirst, P. Rezaie, and K. P.S.J. Murphy (2006)
Hum. Mol. Genet. 15, 1690-1703
   Abstract »    Full Text »    PDF »
Extended Polyglutamine Tracts Cause Aggregation and Structural Perturbation of an Adjacent beta Barrel Protein.
Z. Ignatova and L. M. Gierasch (2006)
J. Biol. Chem. 281, 12959-12967
   Abstract »    Full Text »    PDF »
Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles.
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. (2006)
Brain 129, 877-886
   Abstract »    Full Text »    PDF »
Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases.
T. Gidalevitz, A. Ben-Zvi, K. H. Ho, H. R. Brignull, and R. I. Morimoto (2006)
Science 311, 1471-1474
   Abstract »    Full Text »    PDF »
Huntingtin and Mutant SOD1 Form Aggregate Structures with Distinct Molecular Properties in Human Cells.
G. Matsumoto, S. Kim, and R. I. Morimoto (2006)
J. Biol. Chem. 281, 4477-4485
   Abstract »    Full Text »    PDF »
Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.
A. Haacke, S. A. Broadley, R. Boteva, N. Tzvetkov, F. U. Hartl, and P. Breuer (2006)
Hum. Mol. Genet. 15, 555-568
   Abstract »    Full Text »    PDF »
Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion.
Z. Berger, J. E. Davies, S. Luo, M. Y. Pasco, I. Majoul, C. J. O'Kane, and D. C. Rubinsztein (2006)
Hum. Mol. Genet. 15, 453-465
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Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REG{gamma} as a therapeutic target.
J. S. Bett, G. M. Goellner, B. Woodman, G. Pratt, M. Rechsteiner, and G. P. Bates (2006)
Hum. Mol. Genet. 15, 33-44
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Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity.
J.-Y. Shin, Z.-H. Fang, Z.-X. Yu, C.-E. Wang, S.-H. Li, and X.-J. Li (2005)
J. Cell Biol. 171, 1001-1012
   Abstract »    Full Text »    PDF »
The Ubiquitin-Proteasome System in Huntington's Disease.
A. G. Valera, M. Diaz-Hernandez, F. HernANdez, Z. Ortega, and J. J. Lucas (2005)
Neuroscientist 11, 583-594
   Abstract »    PDF »
Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease.
C. Vacher, L. Garcia-Oroz, and D. C. Rubinsztein (2005)
Hum. Mol. Genet. 14, 3425-3433
   Abstract »    Full Text »    PDF »
Neuroanatomical Phenotyping in the Mouse: The Dopaminergic System.
C. J. Zeiss (2005)
Vet. Pathol. 42, 753-773
   Abstract »    Full Text »    PDF »
Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease.
C. L. Benn, C. Landles, H. Li, A. D. Strand, B. Woodman, K. Sathasivam, S.-H. Li, S. Ghazi-Noori, E. Hockly, S. M.N.N. Faruque, et al. (2005)
Hum. Mol. Genet. 14, 3065-3078
   Abstract »    Full Text »    PDF »
Small molecule intervention in microtubule-associated human disease.
J. M. Gerdes and N. Katsanis (2005)
Hum. Mol. Genet. 14, R291-R300
   Abstract »    Full Text »    PDF »
Active HSF1 Significantly Suppresses Polyglutamine Aggregate Formation in Cellular and Mouse Models.
M. Fujimoto, E. Takaki, T. Hayashi, Y. Kitaura, Y. Tanaka, S. Inouye, and A. Nakai (2005)
J. Biol. Chem. 280, 34908-34916
   Abstract »    Full Text »    PDF »
Drosophila: A "Model" Model System To Study Neurodegeneration.
A. M. Celotto and M. J. Palladino (2005)
Mol. Interv. 5, 292-303
   Abstract »    Full Text »    PDF »
Nuclear Aggresomes Form by Fusion of PML-associated Aggregates.
L. Fu, Y.-s. Gao, A. Tousson, A. Shah, T.-L. L. Chen, B. M. Vertel, and E. Sztul (2005)
Mol. Biol. Cell 16, 4905-4917
   Abstract »    Full Text »    PDF »
Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy.
A. Sanbe, H. Osinska, C. Villa, J. Gulick, R. Klevitsky, C. G. Glabe, R. Kayed, and J. Robbins (2005)
PNAS 102, 13592-13597
   Abstract »    Full Text »    PDF »
Unraveling a role for dopamine in Huntington's disease: The dual role of reactive oxygen species and D2 receptor stimulation.
D. Charvin, P. Vanhoutte, C. Pages, E. Borrelli, and J. Caboche (2005)
PNAS 102, 12218-12223
   Abstract »    Full Text »    PDF »
Frontotemporal dementia with ubiquitinated neuronal inclusions and visuospatial impairment.
Z. Meiner, J. P. Newman, H. Rosenman, D. Soffer, and I. Steiner (2005)
Neurology 65, 478-480
   Abstract »    Full Text »    PDF »
Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies.
W. J. Wolfgang, T. W. Miller, J. M. Webster, J. S. Huston, L. M. Thompson, J. L. Marsh, and A. Messer (2005)
PNAS 102, 11563-11568
   Abstract »    Full Text »    PDF »
A Precipitating Role for Truncated {alpha}-Synuclein and the Proteasome in {alpha}-Synuclein Aggregation: IMPLICATIONS FOR PATHOGENESIS OF PARKINSON DISEASE.
C.-W. Liu, B. I. Giasson, K. A. Lewis, V. M. Lee, G. N. DeMartino, and P. J. Thomas (2005)
J. Biol. Chem. 280, 22670-22678
   Abstract »    Full Text »    PDF »
Thalamic Atrophy in Huntington's Disease Co-varies with Cognitive Performance: A Morphometric MRI Analysis.
J. Kassubek, F. D. Juengling, D. Ecker, and G. B. Landwehrmeyer (2005)
Cereb Cortex 15, 846-853
   Abstract »    Full Text »    PDF »
Striatal Potassium Channel Dysfunction in Huntington's Disease Transgenic Mice.
M. A. Ariano, C. Cepeda, C. R. Calvert, J. Flores-Hernandez, E. Hernandez-Echeagaray, G. J. Klapstein, S. H. Chandler, N. Aronin, M. DiFiglia, and M. S. Levine (2005)
J Neurophysiol 93, 2565-2574
   Abstract »    Full Text »    PDF »
The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation.
B. G. Burnett and R. N. Pittman (2005)
PNAS 102, 4330-4335
   Abstract »    Full Text »    PDF »
A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure.
M. A. Poirier, H. Jiang, and C. A. Ross (2005)
Hum. Mol. Genet. 14, 765-774
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Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis.
T.-K. Sang, C. Li, W. Liu, A. Rodriguez, J. M. Abrams, S. L. Zipursky, and G. R. Jackson (2005)
Hum. Mol. Genet. 14, 357-372
   Abstract »    Full Text »    PDF »
The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice.
W. Mi, B. Beirowski, T. H. Gillingwater, R. Adalbert, D. Wagner, D. Grumme, H. Osaka, L. Conforti, S. Arnhold, K. Addicks, et al. (2005)
Brain 128, 405-416
   Abstract »    Full Text »    PDF »


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