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Title: | HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients | Authors: | Guo, Wenting Naujock, Maximilian Fumagalli, Laura Vandoorne, Tijs Baatsen, Pieter Boon, Ruben Ordovas, Laura Patel, Abdulsamie Welters, Marc Vanwelden, Thomas Geens, Natasja Tricot, Tine Benoy, Veronick Steyaert, Jolien Lefebvre-Omar, Cynthia BOESMANS, Werend Jarpe, Matthew Sterneckert, Jared Wegner, Florian Petri, Susanne Bohl, Delphine Vanden Berghe, Pieter Robberecht, Wim Van Damme, Philip Verfaillie, Catherine Van den Bosch, Ludo |
Issue Date: | 2017 | Source: | NATURE COMMUNICATIONS, 8 (Art N° 861) | 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. | Document URI: | http://hdl.handle.net/1942/29887 | e-ISSN: | 2041-1723 | DOI: | 10.1038/s41467-017-00911-y | ISI #: | 000412775700001 | Rights: | Open access.This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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