The DOI matches its Crossref record; 87 of the 88 references it cites were found in a registry or an index.
HDAC6 inhibition restores TDP‐43 pathology and axonal transport defects in human motor neurons with TARDBP mutations
Open accessAbstract
TDP‐43 is the major component of pathological inclusions in most ALS patients and in up to 50% of patients with frontotemporal dementia (FTD). Heterozygous missense mutations in TARDBP , the gene encoding TDP‐43, are one of the common causes of familial ALS. In this study, we investigate TDP‐43 protein behavior in induced pluripotent stem cell (iPSC)‐derived motor neurons from three ALS patients with different TARDBP mutations, three healthy controls and an isogenic control. TARDPB mutations induce several TDP‐43 changes in spinal motor neurons, including cytoplasmic mislocalization and accumulation of insoluble TDP‐43, C‐terminal fragments, and phospho‐TDP‐43. By generating iPSC lines with allele‐specific tagging of TDP‐43, we find that mutant TDP‐43 initiates the observed disease phenotypes and has an altered interactome as indicated by mass spectrometry. Our findings also indicate that TDP‐43 proteinopathy results in a defect in mitochondrial transport. Lastly, we show that pharmacological inhibition of histone deacetylase 6 (HDAC6) restores the observed TDP‐43 pathologies and the axonal mitochondrial motility, suggesting that HDAC6 inhibition may be an interesting therapeutic target for neurodegenerative disorders linked to TDP‐43 pathology.
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“Notably, genetic knockdown and pharmacological inhibition of HDACs have been shown to ameliorate ALS pathology in different ALS models.341–344”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [343]
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TDP-43 and ALS - what's wrong with my membranes?
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Metadata
- Authors
- Fazal, R., Boeynaems, S., Swijsen, A., De Decker, M., Fumagalli, L., Moisse, M., Vanneste, J., Guo, W., Boon, R., Vercruysse, T., Eggermont, K., Swinnen, B., Beckers, J., Pakravan, D., Vandoorne, T., Vanden Berghe, P., Verfaillie, C., Van Den Bosch, L., & Van Damme, P.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Stanford Medicine (US)
- Leuven Stem Cell Institute (BE)
- Rega Institute for Medical Research (BE)
- Universitair Ziekenhuis Leuven (BE)
- ORCID
- Venue
- The EMBO Journal
- Published
- 2021-03-10
- Volume
- 40
- Issue
- 7
- Pages
- e106177-e106177
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC8013789
- OpenAlex
- W3133763219
- Cited by
- 108
- References
- 88
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 26 · 2023: 18 · 2022: 19 · 2021: 5
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The EMBO Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Funders
- Onderzoeksraad, KU Leuven (C1 ‐ C14‐17‐107)
- Katholieke Universiteit Leuven | Universitaire Ziekenhuizen Leuven, KU Leuven (C1 ‐ C14‐17‐107)
- Alzheimer's Research Foundation (SAO‐FRA n{degree sign} 2017/023)
- VIND (135043)
- Fonds Wetenschappelijk Onderzoek (G.0909.15, G0A7418N)
- Agentschap voor Innovatie door Wetenschap en Technologie (150031)
- The european E‐Rare‐3 project INTEGRALS
- The ALS Liga Belgie
- KULeuven fund "een hart voor ALS"
- Laeversfonds voor ALS onderzoek
- Valery Perrier Race against ALS fund
- National lottery Belgium
- Target ALS
- E. von Behring Chair for Neuromuscular Disorders
- EMBO Long‐term Fellowship
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- TDP-43, TARDBP mutations, HDAC6 inhibition, amyotrophic lateral sclerosis, motor neurons, axonal transport, mitochondrial transport, proteinopathies, TDP-43 mislocalization, protein-protein interaction network, iPSC-derived motor neurons, frontotemporal dementia, therapeutic target
- MeSH terms
- Histone Deacetylase 6, Amyotrophic Lateral Sclerosis, Axonal Transport, Cells, Cultured, DNA-Binding Proteins, Humans, Mitochondria, Motor Neurons, Mutation, Missense, Histone Deacetylase Inhibitors, Induced Pluripotent Stem Cells
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