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

Author

Listed:
  • Wenting Guo

    (Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
    Laboratory of Neurobiology)

  • Maximilian Naujock

    (Hannover Medical School
    Boehringer Ingelheim Pharma GmbH & Co. KG)

  • Laura Fumagalli

    (Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
    Laboratory of Neurobiology)

  • Tijs Vandoorne

    (Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
    Laboratory of Neurobiology)

  • Pieter Baatsen

    (Center for Brain and Disease Research)

  • Ruben Boon

    (KU Leuven-Stem Cell Institute (SCIL))

  • Laura Ordovás

    (KU Leuven-Stem Cell Institute (SCIL)
    Aragon I+D Foundation (ARAID)
    University of Zaragoza)

  • 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)
    Laboratory of Neurobiology)

  • Tine Tricot

    (KU Leuven-Stem Cell Institute (SCIL))

  • Veronick Benoy

    (Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
    Laboratory of Neurobiology)

  • Jolien Steyaert

    (Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
    Laboratory of Neurobiology)

  • 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)
    Department of Neurology)

  • Philip Van Damme

    (Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
    Laboratory of Neurobiology
    Department of Neurology)

  • Catherine Verfaillie

    (KU Leuven-Stem Cell Institute (SCIL))

  • Ludo Van Den Bosch

    (Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND)
    Laboratory of Neurobiology)

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.

Suggested Citation

  • Wenting Guo & Maximilian Naujock & Laura Fumagalli & Tijs Vandoorne & Pieter Baatsen & Ruben Boon & Laura Ordovás & Abdulsamie Patel & Marc Welters & Thomas Vanwelden & Natasja Geens & Tine Tricot & V, 2017. "HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00911-y
    DOI: 10.1038/s41467-017-00911-y
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    Cited by:

    1. Alexis Osseni & Aymeric Ravel-Chapuis & Edwige Belotti & Isabella Scionti & Yann-Gaël Gangloff & Vincent Moncollin & Laetitia Mazelin & Remi Mounier & Pascal Leblanc & Bernard J. Jasmin & Laurent Scha, 2022. "Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Saumyak Mukherjee & Lars V. Schäfer, 2023. "Thermodynamic forces from protein and water govern condensate formation of an intrinsically disordered protein domain," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Severin Lechner & Raphael R. Steimbach & Longlong Wang & Marshall L. Deline & Yun-Chien Chang & Tobias Fromme & Martin Klingenspor & Patrick Matthias & Aubry K. Miller & Guillaume Médard & Bernhard Ku, 2023. "Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Manohar Kodavati & Haibo Wang & Wenting Guo & Joy Mitra & Pavana M. Hegde & Vincent Provasek & Vikas H. Maloji Rao & Indira Vedula & Aijun Zhang & Sankar Mitra & Alan E. Tomkinson & Dale J. Hamilton &, 2024. "FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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