Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-00911-y
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Funding
- KU Leuven
- Fund for Scientific Research Flanders (FWO-Vlaanderen)
- Agency for Innovation by Science and Technology (IWT)
- Belgian Government (Interuniversity Attraction Poles Programme) [P7/16]
- Thierry Latran Foundation
- Association Belge contre les Maladies neuro-Musculaires (ABMM)
- FWO-Vlaanderen under E-RARE-2
- ERA-Net for Research on Rare Diseases (PYRAMID)
- EU Joint Programme - Neurodegenerative Disease Research (JPND) project (STRENGTH)
- ALS Liga Belgie
- Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND)
- China Scholarship Council (CSC)
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- European Research Council under the European's Seventh Framework Programme [340429]
- Deutsche Gesellschaft fur Muskelkranke
- Initiative Therapieforschung ALS
- ANR (LabEx Revive, Investissement d'Avenir) [ANR-10-LABX-73]
- Association Francaise contre les Myopathies (AFM) [16465]
- Agency for Innovation by Science and Technology (SBO-iPSCAF)
- EU Joint Programme - Neurodegenerative Disease Research (JPND) project (RiMod-FTD)
- Geneeskundige Stichting Koningin Elisabeth (G.S.K.E.)
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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 a-tubulin acetylation, endoplasmic reticulum (ER)-mitochondrial overlay, and restore the axonal transport defects in patient-derived MNs.
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