Nuclear and Neuropil Aggregates in Huntington’s Disease: Relationship to Neuropathology
Open accessAbstract
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.
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Mutant huntingtin has a propensity to aggregate in the nucleus and cytoplasm, in dendrites and dendritic spines, in human HD patients and animal models.
“Mutant huntingtin, however, has a propensity to aggregate in the nucleus and in the cytoplasm, which is reported both in human HD patients and in animal models, in dendrites as well as in dendritic spines (Di-Figlia et al., 1997;Scherzinger et al., 1997;Gutekunst et al., 1999;Lunkes et al., 2002).”
From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Gutekunst et al., 1999
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“The width of the filaments was ;10 nm, which is similar to those observed in huntingtin aggregates in exon-1 HD transgenic mice (Davies et al., 1997) and in vitro ( Scherzinger et al., 1997 ).”
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“Mutant huntingtin, however, has a propensity to aggregate in the nucleus and in the cytoplasm, which is reported both in human HD patients and in animal models, in dendrites as well as in dendritic spines (DiFiglia et al., 1997; Scherzinger et al., 1997; Gutekunst et al., 1999; Lunkes et al., 2002).”
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- Authors
- Gutekunst, C.-A., Li, S.-H., Yi, H., Mulroy, J. S., Kuemmerle, S., Jones, R., Rye, D., Ferrante, R. J., Hersch, S. M., & Li, X.-J.
- Affiliations
- Emory University (US)
- Pediatrics and Genetics (US)
- Boston University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1999-04-01
- Volume
- 19
- Issue
- 7
- Pages
- 2522-2534
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6786077
- OpenAlex
- W1962249623
- Cited by
- 914
- References
- 2
- Citations by year
- 2026: 12 · 2025: 26 · 2024: 29 · 2023: 20 · 2022: 32 · 2021: 31 · 2020: 32 · 2019: 22 · 2018: 24 · 2017: 22 · 2016: 28 · 2015: 41 · 2014: 39 · 2013: 34 · 2012: 37
- FWCI
- 16.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Emory University
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS 35255, NS 36232, R01NS036232, R01NS035255)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Huntington's disease, huntingtin aggregates, nuclear aggregates, neuronal cell death, dendritic pathology, dendritic spines, striatum, cortex, ubiquitination, ubiquitin-mediated proteolysis, presymptomatic disease, neuropathology
- MeSH terms
- Amino Acid Sequence, Antibody Formation, Cell Nucleus, Humans, Huntington Disease, Molecular Sequence Data, Neurons, Recombinant Fusion Proteins, Cell Death, Neuropil
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