The long and the short of aberrant ciliogenesis in Huntington disease
Open accessAbstract
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that is caused by a mutant huntingtin (HTT) gene encoding a version of the Htt protein with an expanded polyglutamine stretch. Although the HTT gene was discovered more than 18 years ago, the functions of normal Htt and the mechanisms by which mutant Htt causes disease are not well defined. In this issue of the JCI, Keryer et al. uncovered a novel function for normal Htt in ciliogenesis and report that mutant Htt causes hypermorphic ciliogenesis and ciliary dysfunction. These observations suggest that it is now critical to understand the extent to which ciliary dysfunction contributes to the different symptoms of HD and to determine whether therapeutic strategies designed to normalize ciliary function can ameliorate the disease.
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Pathogenic polyQ-HTT promotes accumulation of huntingtin-associated protein 1 and pericentriolar material 1 at the centrosome in Huntington's disease neurons.
“Pathogenic polyQ-HTT promotes the accumulation of huntingtin-associated protein 1 (HAP1) and pericentriolar material 1 (PCM1) at the centrosome, leading to elongation of PC and accumulation of N-acetylated tubulin in HD neurons [54,179].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [179]
“A novel function for Htt in ciliogenesis” reports that mutant Htt causes excess PCM1 to accumulate at the centrosome. Figure 2 says it is not yet known whether HAP1 is associated with mutant Htt or PCM1 at the centrosome, so the claimed accumulation of HAP1 there is not supported. (LLM, conf=0.91)
Experimental — accuracy not yet measuredThis accumulation leads to elongation of primary cilia in Huntington's disease neurons.
“Pathogenic polyQ-HTT promotes the accumulation of huntingtin-associated protein 1 (HAP1) and pericentriolar material 1 (PCM1) at the centrosome, leading to elongation of PC and accumulation of N-acetylated tubulin in HD neurons [54,179].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [179]
Figure 2 links mutant huntingtin–associated PCM1 accumulation at the centrosome with lengthening of primary cilia. However, “A novel function for Htt in ciliogenesis” reports an increased percentage of neurons and glia with primary cilia in vitro, while the cilia specifically reported as lengthened were ependymal-cell cilia in an HD mouse model. The copy therefore does not establish elongation of primary cilia specifically in HD neurons. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThis accumulation leads to accumulation of N-acetylated tubulin in Huntington's disease neurons.
“Pathogenic polyQ-HTT promotes the accumulation of huntingtin-associated protein 1 (HAP1) and pericentriolar material 1 (PCM1) at the centrosome, leading to elongation of PC and accumulation of N-acetylated tubulin in HD neurons [54,179].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [179]
The ‘A novel function for Htt in ciliogenesis’ section reports increased PCM1 and N-acetylated tubulin immunoreactivity in postmortem HD brains. Figure 2 links centrosomal PCM1 accumulation to increased ciliogenesis, but the paper does not establish that this accumulation causes N-acetylated tubulin to accumulate specifically in HD neurons. No page number is available in our copy. (LLM, conf=0.84)
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Sorted by citations
Danna, R., Kondle, S., Amar, O., Mabourakh, M., Chen, G., Fadol, W. B., & Mohieldin, A. M. (2025) · Biology · doi:10.3390/biology14121787 · Cited by 2 · see citing works
“Primary Cilia, Exosomes, and TNTs in Huntington’s Disease Pathogenic polyQ-HTT promotes the accumulation of huntingtin-associated protein 1 (HAP1) and pericentriolar material 1 (PCM1) at the centrosome, leading to elongation of PC and accumulation of N-acetylated tubulin in HD neurons [54,179].”
- Authors
- Liu, J.-P., & Zeitlin, S. O.
- Affiliations
- University of Virginia (US)
- University of Michigan (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2011-11-01
- Volume
- 121
- Issue
- 11
- Pages
- 4237-4241
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3204854
- OpenAlex
- W1980272282
- Cited by
- 19
- References
- 23
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2021: 1 · 2019: 1 · 2017: 1 · 2015: 1 · 2014: 1 · 2013: 5 · 2012: 2
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- CHDI Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS043466, R01NS043466, R56NS043466)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- Huntington's disease, ciliogenesis, mutant huntingtin, polyglutamine expansion, ciliary dysfunction, neurodegeneration
- MeSH terms
- Huntingtin Protein, Animals, Autoantigens, Humans, Huntington Disease, Nerve Tissue Proteins, Nuclear Proteins, Cell Cycle Proteins, Mutant Proteins
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