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Nat Commun. 2017 Oct 11;8(1):861. doi: 10.1038/s41467-017-00911-y.

HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients.

Author information

1
KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), Leuven, 3000, Belgium.
2
VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, 3000, Belgium.
3
Department of Neurology, Hannover Medical School, Hannover, 30625, Germany.
4
CNS Research Department, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, 88400, Germany.
5
VIB Bio Imaging Core and VIB-KU Leuven, Center for Brain and Disease Research, Leuven, 3000, Belgium.
6
KU Leuven-Stem Cell Institute (SCIL), Leuven, 3000, Belgium.
7
Aragon I+D Foundation (ARAID), Zaragoza, 50018, Spain.
8
Biomedical Signal Interpretation and Computational Simulation (BSICoS) Group, Aragon Institute of Engineering Research, IIS Aragón, University of Zaragoza, Zaragoza, 50018, Spain.
9
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 6, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, 75013, France.
10
Lab for Enteric NeuroScience, TARGID, KU Leuven, Leuven, 3000, Belgium.
11
Acetylon Pharmaceuticals Inc., Boston, MA, 02210, USA.
12
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, 01069, Germany.
13
University Hospitals Leuven, Department of Neurology, Leuven, 3000, Belgium.
14
KU Leuven-Stem Cell Institute (SCIL), Leuven, 3000, Belgium. Catherine.Verfaillie@med.kuleuven.be.
15
KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), Leuven, 3000, Belgium. Ludo.Vandenbosch@kuleuven.vib.be.
16
VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, 3000, Belgium. Ludo.Vandenbosch@kuleuven.vib.be.

Abstract

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.Amyotrophic lateral sclerosis (ALS) leads to selective loss of motor neurons. Using motor neurons derived from induced pluripotent stem cells from patients with ALS and FUS mutations, the authors demonstrate that axonal transport deficits that are observed in these cells can be rescued by HDAC6 inhibition.

PMID:
29021520
PMCID:
PMC5636840
DOI:
10.1038/s41467-017-00911-y
[Indexed for MEDLINE]
Free PMC Article

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