Nuclear and neuropil aggregates in Huntington's disease: Relationship to neuropathology

• Type of Material: Article
• Authors: Shihua Li, Emory University; Claire-Anne Gutekunst, Emory University; Hong Yi, Emory University; James S. Mulroy, Emory University; Stefan Kuemmerle, Bedford VA Medical Center; Randi Jones, Emory University; David Rye, Emory University; Robert J. Ferrante, Emory University; Steven M. Hersch, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 1999-04-01
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 1999 Society for Neuroscience
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/jneurosci.19-07-02522.1999
• Title of Journal or Parent Work: Journal of Neuroscience
• Volume: 19
• Issue: 7
• Start Page: 2522
• End Page: 2534
• Grant/Funding Information: This work was supported by National Institutes of Health Grants NS36232 (X.-J.L.) and NS35255 (S.M.H., C.-A.G., R.J.F.), The Hereditary Disease Foundation and The Wills Foundation (X.-J.L.), the Huntington’s Disease Society of America (R.J.F., X.-J.L.,S.M.H.), the Veteran’s Administration (R.J.F.), and the Emory Huntington’s Disease Society of America Center of Excellence for Family Services (S.M.H., R.J.). S.K. is a medical student from Technische Universitaet Muenchen Medical School, Munich, Germany.
• Keywords: Science & Technology; GLUTAMINE REPEATS; neuropil aggregates; DEGENERATION; LOCALIZATION; BRAIN; Neurosciences & Neurology; Huntington's disease; Life Sciences & Biomedicine; neuropathology; NEUROLOGICAL PHENOTYPE; EXPRESSION; CORTEX; Neurosciences; huntingtin; nuclear inclusions; NEURONAL INTRANUCLEAR INCLUSIONS; PROTEIN; ubiquitin; SPINY NEURONS
• Research Categories: Biology, Neuroscience

Abstract

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.