HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder due to selective loss of motor neurons (MNs). Mutations in the fused in sarcoma (FUS) gene can cause both juvenile and late onset ALS. We generated and characterized induced pluripotent stem cells (iPSCs) from ALS patients with different FUS mutations, as well as from healthy controls. Patient-derived MNs show typical cytoplasmic FUS pathology, hypoexcitability, as well as progressive axonal transport defects. Axonal transport defects are rescued by CRISPR/Cas9-mediated genetic correction of the FUS mutation in patient-derived iPSCs. Moreover, these defects are reproduced by expressing mutant FUS in human embryonic stem cells (hESCs), whereas knockdown of endogenous FUS has no effect, confirming that these pathological changes are mutant FUS dependent. Pharmacological inhibition as well as genetic silencing of histone deacetylase 6 (HDAC6) increase α-tubulin acetylation, endoplasmic reticulum (ER)–mitochondrial overlay, and restore the axonal transport defects in patient-derived MNs.
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Genetic knockdown and pharmacological inhibition of HDACs ameliorate ALS pathology in different ALS models.
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- Authors
- Guo, W., Naujock, M., Fumagalli, L., Vandoorne, T., Baatsen, P., Boon, R., Ordovás, L., Patel, A., Welters, M., Vanwelden, T., Geens, N., Tricot, T., Benoy, V., Steyaert, J., Lefebvre-Omar, C., Boesmans, W., Jarpe, M., Sterneckert, J., Wegner, F., Petri, S., Bohl, D., Vanden Berghe, P., Robberecht, W., Van Damme, P., Verfaillie, C., & Van Den Bosch, L.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Boehringer Ingelheim (Germany) (DE)
- Leuven Stem Cell Institute (BE)
- Universidad de Zaragoza (ES)
- Centre National de la Recherche Scientifique (FR)
- KU Leuven (BE)
- Acetylon Pharmaceuticals (United States) (US)
- Center for Regenerative Therapies Dresden (DE)
- Medizinische Hochschule Hannover (DE)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Verfaillie, Catherine
- ORCID
- Venue
- Nature Communications
- Published
- 2017-10-11
- Volume
- 8
- Issue
- 1
- Pages
- 861-861
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5636840
- OpenAlex
- W2763212735
- Cited by
- 373
- References
- 57
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 44 · 2023: 47 · 2022: 46 · 2021: 52 · 2020: 45 · 2019: 51 · 2018: 20 · 2017: 2
- FWCI
- 22.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Document Server@UHasselt (UHasselt) (submittedVersion, other-oa)
- Zaguan (University of Zaragoza Repository) (submittedVersion, cc-by)
- Funders
- Association Belge contre les Maladies Neuro-Musculaires
- EU Joint Programme – Neurodegenerative Disease Research
- E-Rare
- Agence Nationale de la Recherche (ANR-10-LABX73, ANR-13-JPRF-0003, ANR-13-JPRF-0004, ANR-10, ANR-10-LABX, ANR-10-LABX-0073, 10-LABX-73)
- Belgian Federal Science Policy Office (P7/16)
- Fonds Wetenschappelijk Onderzoek
- KU Leuven (KU Leuven (C1)
- China Scholarship Council
- Deutsche Gesellschaft für Muskelkranke
- Vlaamse regering
- FP7 Ideas: European Research Council (340429)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- amyotrophic lateral sclerosis, FUS mutations, HDAC6 inhibition, motor neurons, induced pluripotent stem cells, alpha-tubulin acetylation, CRISPR/Cas9 gene correction, patient-derived iPSCs
- MeSH terms
- Histone Deacetylase 6, Adolescent, Adult, Aged, Amyotrophic Lateral Sclerosis, Axonal Transport, Female, Humans, Hydroxamic Acids, Indoles, Male, Motor Neurons, Pyrimidines, Point Mutation, RNA-Binding Protein FUS, Induced Pluripotent Stem Cells, Primary Cell Culture, CRISPR-Cas Systems
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