Cited by 163Genetic Neurodegenerative DiseasesPrion Diseases and Protein MisfoldingLysosomal Storage Disorders Research

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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

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Mende-Mueller, Liane M., Toneff, Thomas, Hwang, Shin-Rong, Chesselet, Marie-Francoise, Hook, Vivian Y. H.·2001·The Journal of Neuroscience

DOI 10.1523/jneurosci.21-06-01830.2001PMC PMC6762596

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Abstract

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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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
DOI: 10.1523/jneurosci.21-06-01830.2001
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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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

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