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

Guo, Wenting ; Naujock, Maximilian ; Fumagalli, Laura ; Vandoorne, Tijs ; Baatsen, Pieter ; Boon, Ruben ; Ordovás, 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
HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients
Resumen: 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.
Idioma: Inglés
DOI: 10.1038/s41467-017-00911-y
Año: 2017
Publicado en: NATURE COMMUNICATIONS 8 (2017), 861 [15 pp]
ISSN: 2041-1723

Tipo y forma: Artículo (Versión definitiva)

Creative Commons Debe reconocer adecuadamente la autoría, proporcionar un enlace a la licencia e indicar si se han realizado cambios. Puede hacerlo de cualquier manera razonable, pero no de una manera que sugiera que tiene el apoyo del licenciador o lo recibe por el uso que hace.


Exportado de SIDERAL (2017-11-09-11:57:56)

Este artículo se encuentra en las siguientes colecciones:
Artículos



 Registro creado el 2017-11-09, última modificación el 2017-11-09


Versión publicada:
 PDF
Valore este documento:

Rate this document:
1
2
3
 
(Sin ninguna reseña)