Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder due to selective loss of motor neurons (MNs). Previous research to understand pathogenic ALS mechanisms is mainly based on rodent models overexpressing a mutant gene and many potential therapies for ALS have been unsuccessful in human clinical trials. The cell reprogramming technology which enables the generation of human induced pluripotent stem cells (hiPSCs) from human somatic cells, gave researchers a new opportunity to obtain human MNs by adding small molecules. As a patient derived in vitro model, the iPSC model is convenient for investigating mechanism, selecting potential biomarkers as well drug screening.
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 progressive axonal transport defects which is in line with clinic symptoms of ALS. 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 of histone deacetylase 6 (HDAC6) increase α-tubulin acetylation and restore the axonal transport defects in patient-derived MNs. Here we propose HDAC6 inhibitors which has been used for cancer as a promising drug candidates for treating ALS disease.