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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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