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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
Open accessAbstract
Proteolysis of mutant huntingtin (htt) has been hypothesized to occur in Huntington's disease (HD) brains. Therefore, this in vivo study examined htt fragments in cortex and striatum of adult HD and control human brains by Western blots, using domain-specific anti-htt antibodies that recognize N- and C-terminal domains of htt (residues 181-810 and 2146-2541, respectively), as well as the 17 residues at the N terminus of htt. On the basis of the patterns of htt fragments observed, different "protease-susceptible domains" were identified for proteolysis of htt in cortex compared with striatum, suggesting that htt undergoes tissue-specific proteolysis. In cortex, htt proteolysis occurs within two different N-terminal domains, termed protease-susceptible domains "A" and "B." However, in striatum, a different pattern of fragments indicated that proteolysis of striatal htt occurred within a C-terminal domain termed "C," as well as within the N-terminal domain region designated "A". Importantly, striatum from HD brains showed elevated levels of 40-50 kDa N-terminal and 30-50 kDa C-terminal fragments compared with that of controls. Increased levels of these htt fragments may occur from a combination of enhanced production or retarded degradation of fragments. Results also demonstrated tissue-specific ubiquitination of certain htt N-terminal fragments in striatum compared with cortex. Moreover, expansions of the triplet-repeat domain of the IT15 gene encoding htt was confirmed for the HD tissue samples studied. Thus, regulated tissue-specific proteolysis and ubiquitination of htt occur in human HD brains. These results suggest that the role of huntingtin proteolysis should be explored in the pathogenic mechanisms of HD.
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“The unstable CAG repeats in exon 1 of HTT encode the N-terminal polyglutamine tract of the ~350 kDa, ~3100 amino acid huntingtin protein [163].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [163]
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Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., & Finkbeiner, S. (2004) · Nature · doi:10.1038/nature02998 · Cited by 1,979
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Metadata
- Authors
- Mende-Mueller, L. M., Toneff, T., Hwang, S.-R., Chesselet, M.-F., & Hook, V. Y. H.
- Affiliations
- Buck Institute for Research on Aging (US)
- ORCID
- Hook, Vivian Y. H.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-03-15
- Volume
- 21
- Issue
- 6
- Pages
- 1830-1837
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762596
- OpenAlex
- W2101847922
- Cited by
- 163
- References
- 26
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 10 · 2018: 9 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 6 · 2013: 3 · 2012: 8
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hereditary Disease Foundation
- National Institute of Mental Health (MH.NS 31862)
- National Cancer Institute (R01CA092126)
- 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
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- huntingtin, Huntington's disease, proteolysis, striatum, cerebral cortex, N-terminal fragment, C-terminal fragment, ubiquitination, trinucleotide repeat expansion, IT15 gene
- MeSH terms
- Huntingtin Protein, Aged, Antibody Specificity, Brain, Cerebral Cortex, Corpus Striatum, Humans, Huntington Disease, Middle Aged, Nerve Tissue Proteins, Nuclear Proteins, Organ Specificity, Peptide Fragments, Peptide Hydrolases, Putamen, Ubiquitins, Blotting, Western, Polymerase Chain Reaction, Protein Structure, Tertiary, Trinucleotide Repeat Expansion
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