Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia
Abstract
Expansion of GAA x TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the molecular basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these molecules directly affect the histones associated with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia.
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The I63T mutant Cp isoform is expressed at half the normal level and displays a distinct decrease in ferroxidase activity in vivo.
“In further investigation, the I63T mutant Cp isoform was expressed at half the normal level and displayed a distinct decrease in ferroxidase activity in vivo.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [135]
The D544E Cp is expressed at lower levels and exhibits decreased ferroxidase activity.
“The D544E Cp was expressed at lower levels and exhibited decreased ferroxidase activity (135).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [135]
Retention of the I63T mutant Cp isoform in the endoplasmic reticulum may lead to cell death.
“In addition, retention of the I63T mutant Cp isoform in the endoplasmic reticulum (ER) may lead to cell death.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [135]
In HEK293 cells, the I63T GPI-linked isoform of Cp remains in the endoplasmic reticulum.
“In HEK293 cells, the I63T GPI-linked isoform of Cp remained in the endoplasmic reticulum.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [135]
Decreased expression of Cp and deficient ferroxidase activity may result in free iron accumulation and decreased antioxidant potential.
“Decreased expression of Cp and deficient ferroxidase activity may result in “free iron” accumulation and decreased antioxidant potential.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [135]
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- Authors
- Herman, D., Jenssen, K., Burnett, R., Soragni, E., Perlman, S. L., & Gottesfeld, J. M.
- Affiliations
- Scripps Research Institute (US)
- University of California, Los Angeles (US)
- Corresponding author
- Gottesfeld, Joel M
- Venue
- Nature Chemical Biology
- Published
- 2006-08-20
- Volume
- 2
- Issue
- 10
- Pages
- 551-558
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2071254988
- Cited by
- 442
- References
- 43
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 12 · 2023: 16 · 2022: 19 · 2021: 13 · 2020: 19 · 2019: 24 · 2018: 19 · 2017: 16 · 2016: 24 · 2015: 30 · 2014: 34 · 2013: 31 · 2012: 37
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Friedreich's Ataxia Research Alliance
- National Institute of Neurological Disorders and Stroke (R21NS048989)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Friedreich's ataxia, histone deacetylase inhibitors, gene silencing, frataxin, intronic repeat expansion, histone acetylation, histone H3K9 trimethylation, primary lymphocytes, neurodegenerative disease treatment
- MeSH terms
- Frataxin, Acetylation, Alleles, Anilides, Cell Line, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Inhibitors, Friedreich Ataxia, Gene Expression Regulation, HeLa Cells, Heterochromatin, Histones, Humans, RNA, Messenger, Transcription, Genetic, Molecular Structure, Gene Silencing, Iron-Binding Proteins, Histone Deacetylase Inhibitors
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