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Updated: Oct 22, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Potential Therapeutic Role of HDAC Inhibitors in FUS-ALS
Clara Tejido1, Donya Pakravan1,2, Ludo Van Den Bosch1,2
1Vlaams Instituut voor Biotechnologie (VIB), Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
Abstract:
Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). However, the exact pathogenic mechanism of mutant fused in sarcoma (FUS) protein is not completely understood. FUS is an RNA binding protein (RBP) localized predominantly in the nucleus, but ALS-linked FUS mutations can affect its nuclear localization signal impairing its import into the nucleus. This mislocalization to the cytoplasm facilitates FUS aggregation in cytoplasmic inclusions. Therapies targeting post translational modifications are rising as new treatments for ALS, in particular acetylation which could have a role in the dynamics of RBPs. Research using histone deacetylase (HDAC) inhibitors in FUS-ALS models showed that HDACs can influence cytoplasmic FUS localization. Inhibition of HDACs could promote acetylation of the FUS RNA binding domain (RRM) and altering its RNA interactions resulting in FUS maintenance in the nucleus. In addition, acetylation of FUS RRMs might also favor or disfavor its incorporation into pathological inclusions. In this review, we summarize and discuss the evidence for the potential role of HDACs in the context of FUS-ALS and we propose a new hypothesis based on this overview.
Insights
Histone deacetylase (HDAC) inhibitors may offer a new therapeutic strategy for amyotrophic lateral sclerosis with FUS mutations (ALS-FUS). Inhibiting HDACs may promote FUS protein acetylation, aiding nuclear retention and reducing toxic cytoplasmic aggregation.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to mutations in the FUS gene (ALS-FUS).
- The precise pathogenic mechanisms of mutant FUS protein, an RNA-binding protein (RBP), remain unclear.
- ALS-linked FUS mutations disrupt nuclear import, leading to cytoplasmic mislocalization and aggregation.
Purpose of the Study:
- To review the role of histone deacetylases (HDACs) in the context of FUS-ALS.
- To explore the potential of targeting post-translational modifications, specifically acetylation, for ALS-FUS therapies.
- To propose a novel hypothesis regarding HDACs' influence on FUS pathology.
Main Methods:
- Review of existing literature on FUS protein, ALS-FUS, RNA-binding proteins, and post-translational modifications.
- Analysis of research utilizing histone deacetylase (HDAC) inhibitors in FUS-ALS models.
- Discussion of the impact of HDAC inhibition on FUS protein localization and aggregation.
Main Results:
- HDACs influence the cytoplasmic localization of FUS in ALS-FUS models.
- Inhibition of HDACs can promote acetylation of the FUS RNA-binding domain (RRM).
- FUS RRM acetylation may alter RNA interactions, promoting nuclear retention and potentially affecting pathological inclusions.
Conclusions:
- HDACs represent a potential therapeutic target for ALS-FUS.
- Modulating FUS acetylation via HDAC inhibition could be a promising treatment strategy.
- Further research is warranted to elucidate the precise mechanisms and therapeutic efficacy.
