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

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the selective loss of motor neurons (MNs). Mutations in the fused in sarcoma (FUS) gene are linked to both juvenile and late-onset forms of ALS. In this study, we generated and characterized induced pluripotent stem cells (iPSCs) from ALS patients with various FUS mutations, alongside healthy control iPSCs.

Motor neurons derived from these patients exhibited typical cytoplasmic FUS pathology, hypoexcitability, and progressive axonal transport defects. Remarkably, these transport defects were corrected through CRISPR/Cas9-mediated genetic correction of the FUS mutation in the patient-derived iPSCs. We also found that expressing mutant FUS in human embryonic stem cells (hESCs) replicated these defects, while knockdown of endogenous FUS had no impact, confirming that these pathological changes are specifically dependent on the mutant FUS.

Furthermore, pharmacological inhibition and genetic silencing of histone deacetylase 6 (HDAC6) led to increased α-tubulin acetylation, enhanced endoplasmic reticulum-mitochondrial interactions, and restored axonal transport in patient-derived MNs. Our findings demonstrate that axonal transport deficits observed in motor neurons from ALS patients with FUS mutations can be ACY-738 effectively rescued through HDAC6 inhibition.