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Previous Article | Next Article
The Journal of Neuroscience, April 1, 1999, 19(7):2522-2534
Nuclear and Neuropil Aggregates in Huntington's Disease: Relationship to Neuropathology
Claire-Anne Gutekunst1, Shi-Hua Li2, Hong Yi1, James S. Mulroy1, Stefan Kuemmerle3, Randi Jones1, David Rye1, Robert J. Ferrante3, Steven M. Hersch1, and Xiao-Jiang Li2 Departments of 1 Neurology and 2 Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, and 3 Geriatric Research Education Clinical Center, Bedford VA Medical Center, Bedford, Massachusetts 01730, and Departments of Neurology, Pathology, and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118
The data we report in this study concern the types, location, numbers, forms, and composition of microscopic huntingtin aggregates in brain tissues from humans with different grades of Huntington's disease (HD). We have developed a fusion protein antibody against the first 256 amino acids that preferentially recognizes aggregated huntingtin and labels many more aggregates in neuronal nuclei, perikarya, and processes in human brain than have been described previously. Using this antibody and human brain tissue ranging from presymptomatic to grade 4, we have compared the numbers and locations of nuclear and neuropil aggregates with the known patterns of neuronal death in HD. We show that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before the onset of clinical symptoms. There are also many more aggregates in cortex than in striatum, where they are actually uncommon. Although the striatum is the most affected region in HD, only 1-4% of striatal neurons in all grades of HD have nuclear aggregates. Neuropil aggregates, which we have identified by electron microscopy to occur in dendrites and dendritic spines, could play a role in the known dendritic pathology that occurs in HD. Aggregates increase in size in advanced grades, suggesting that they may persist in neurons that are more likely to survive. Ubiquitination is apparent in only a subset of aggregates, suggesting that ubiquitin-mediated proteolysis of aggregates may be late or variable.
Key words: Huntington's disease; huntingtin; neuropil aggregates; nuclear inclusions; ubiquitin; neuropathology
Copyright © 1999 Society for Neuroscience 0270-6474/99/1972522-13$05.00/0
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[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]
N. R. Jana, E. A. Zemskov, G.-h. Wang, and N. Nukina
Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release
Hum. Mol. Genet., May 1, 2001; 10(10): 1049 - 1059.
[Abstract] [Full Text] [PDF]
J.-M. Lecerf, T. L. Shirley, Q. Zhu, A. Kazantsev, P. Amersdorfer, D. E. Housman, A. Messer, and J. S. Huston
Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease
PNAS, April 10, 2001; 98(8): 4764 - 4769.
[Abstract] [Full Text] [PDF]
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., April 2, 2001; 153(1): 25 - 34.
[Abstract] [Full Text] [PDF]
L. M. Mende-Mueller, T. Toneff, S.-R. Hwang, M.-F. Chesselet, and V. Y. H. Hook
Tissue-Specific Proteolysis of Huntingtin (htt) in Human Brain: Evidence of Enhanced Levels of N- and C-Terminal htt Fragments in Huntington's Disease Striatum
J. Neurosci., March 15, 2001; 21(6): 1830 - 1837.
[Abstract] [Full Text] [PDF]
S. Holbert, I. Denghien, T. Kiechle, A. Rosenblatt, C. Wellington, M. R. Hayden, R. L. Margolis, C. A. Ross, J. Dausset, R. J. Ferrante, et al.
The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis
PNAS, January 24, 2001; (2001) 41566798.
[Abstract] [Full Text]
T. B. Freeman, F. Cicchetti, R. A. Hauser, T. W. Deacon, X.-J. Li, S. M. Hersch, G. M. Nauert, P. R. Sanberg, J. H. Kordower, S. Saporta, et al.
Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology
PNAS, December 5, 2000; 97(25): 13877 - 13882.
[Abstract] [Full Text] [PDF]
F. Trettel, D. Rigamonti, P. Hilditch-Maguire, V. C. Wheeler, A. H. Sharp, F. Persichetti, E. Cattaneo, and M. E. MacDonald
Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells
Hum. Mol. Genet., November 1, 2000; 9(19): 2799 - 2809.
[Abstract] [Full Text] [PDF]
S.-H. Li, S. Lam, A. L. Cheng, and X.-J. Li
Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis
Hum. Mol. Genet., November 1, 2000; 9(19): 2859 - 2867.
[Abstract] [Full Text] [PDF]
G. Yvert, K. S. Lindenberg, S. Picaud, G. B. Landwehrmeyer, J.-A. Sahel, and J.-L. Mandel
Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice
Hum. Mol. Genet., October 1, 2000; 9(17): 2491 - 2506.
[Abstract] [Full Text] [PDF]
L. A. Passani, M. T. Bedford, P. W. Faber, K. M. McGinnis, A. H. Sharp, J. F. Gusella, J.-P. Vonsattel, and M. E. MacDonald
Huntingtin's WW domain partners in Huntington's disease post-mortem brain fulfill genetic criteria for direct involvement in Huntington's disease pathogenesis
Hum. Mol. Genet., September 1, 2000; 9(14): 2175 - 2182.
[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]
K. P. S. J. Murphy, R. J. Carter, L. A. Lione, L. Mangiarini, A. Mahal, G. P. Bates, S. B. Dunnett, and A. J. Morton
Abnormal Synaptic Plasticity and Impaired Spatial Cognition in Mice Transgenic for Exon 1 of the Human Huntington's Disease Mutation
J. Neurosci., July 1, 2000; 20(13): 5115 - 5123.
[Abstract] [Full Text] [PDF]
R. J. Ferrante, O. A. Andreassen, B. G. Jenkins, A. Dedeoglu, S. Kuemmerle, J. K. Kubilus, R. Kaddurah-Daouk, S. M. Hersch, and M. F. Beal
Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease
J. Neurosci., June 15, 2000; 20(12): 4389 - 4397.
[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]
M. Becker, E. Martin, J. Schneikert, H. F. Krug, and A. C.B. Cato
Cytoplasmic Localization and the Choice of Ligand Determine Aggregate Formation by Androgen Receptor with Amplified Polyglutamine Stretch
J. Cell Biol., April 17, 2000; 149(2): 255 - 262.
[Abstract] [Full Text] [PDF]
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]
V. C. Wheeler, J. K. White, C.-A. Gutekunst, V. Vrbanac, M. Weaver, X.-J. Li, S.-H. Li, H. Yi, J.-P. Vonsattel, J. F. Gusella, et al.
Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice
Hum. Mol. Genet., March 1, 2000; 9(4): 503 - 513.
[Abstract] [Full Text] [PDF]
J. L. Marsh, H. Walker, H. Theisen, Y.-Z. Zhu, T. Fielder, J. Purcell, and L. M. Thompson
Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila
Hum. Mol. Genet., January 1, 2000; 9(1): 13 - 25.
[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]
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]
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