Therapeutic potential of HDAC6 in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults and no effective treatments exist. Mutations in FUS are one of the genetic causes of familial ALS. We used induced pluripotent stem cells (iPSCs) derived from FUS-ALS patients to investigate the pathological mechanism. We observed hypo-excitability, cytoplasmic FUS localization and axonal transport defects of different cargoes in motor neurons differentiated from these iPSCs. Pharmacological inhibition and genetic silencing of histone deacetylase 6 (HDAC6) restored the axonal transport defects. Moreover, the disturbed association between mitochondria and the endoplasmic reticulum (ER) was also reversed by inhibition of HDAC6. The positive effects of HDAC6 inhibition were linked to an increase in the acetylation level of α-tubulin, one of the building blocks of the microtubules. In conclusion, HDAC6 inhibition could be a potential new therapeutic strategy for ALS.