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

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

Factor impacto JCR: 12.353 (2017)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 3 / 64 = 0.047 (2017) - Q1 - T1

Factor impacto SCIMAGO: 6.582 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Tipo y forma: Article (Published version)