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

Wenting Guo, Maximilian Naujock, Laura Fumagalli, Tijs Vandoorne, Pieter Baatsen, Ruben Boon, Laura Ordovás, Abdulsamie Patel, Marc Welters, Thomas Vanwelden, Natasja Geens, Tine Tricot, Veronick Benoy, Jolien Steyaert, Cynthia Lefebvre-Omar, Werend Boesmans, Matthew Jarpe, Jared Sterneckert, Florian Wegner, Susanne Petri, Delphine Bohl, Pieter Vanden Berghe, Wim Robberecht, Philip Van Damme, Catherine Verfaillie () and Ludo Van Den Bosch ()
Additional contact information
Wenting Guo: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Maximilian Naujock: Hannover Medical School
Laura Fumagalli: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Tijs Vandoorne: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Pieter Baatsen: Center for Brain and Disease Research
Ruben Boon: KU Leuven-Stem Cell Institute (SCIL)
Laura Ordovás: KU Leuven-Stem Cell Institute (SCIL)
Abdulsamie Patel: KU Leuven-Stem Cell Institute (SCIL)
Marc Welters: KU Leuven-Stem Cell Institute (SCIL)
Thomas Vanwelden: KU Leuven-Stem Cell Institute (SCIL)
Natasja Geens: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Tine Tricot: KU Leuven-Stem Cell Institute (SCIL)
Veronick Benoy: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Jolien Steyaert: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Cynthia Lefebvre-Omar: Hôpital Pitié-Salpêtrière
Werend Boesmans: TARGID, KU Leuven
Matthew Jarpe: Acetylon Pharmaceuticals Inc.
Jared Sterneckert: Technische Universität Dresden
Florian Wegner: Hannover Medical School
Susanne Petri: Hannover Medical School
Delphine Bohl: Hôpital Pitié-Salpêtrière
Pieter Vanden Berghe: TARGID, KU Leuven
Wim Robberecht: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Philip Van Damme: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
Catherine Verfaillie: KU Leuven-Stem Cell Institute (SCIL)
Ludo Van Den Bosch: Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00911-y

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