ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death

Amyotrophic Lateral Sclerosis (ALS) is a group of neurodegenerative disorders that featured with the death of motor neurons, which leads to loss of voluntary control on muscles. The etiologies vary among different subtypes of ALS, and no effective management or medication could be provided to the patients, with the underlying mechanisms incompletely understood yet. Mutations in human Optn (Optineurin), particularly E478G, have been found in many ALS patients. In this work, we report that NF-kappa B activity was increased in Optn knockout (Optn(-/-)) MEF (mouse embryonic fibroblast) cells expressing OPTN of different ALS-associated mutants especially E478G. Inflammation was significantly activated in mice infected with lenti-virus that allowed overexpression of OPTNE478G mutation in the motor cortex, with marked increase in the secretion of pro-inflammatory cytokines as well as neuronal cell death. Our work with both cell and animal models strongly suggested that anti-inflammation treatment could represent a powerful strategy to intervene into disease progression in ALS patients who possess the distinctive mutations in OPTN gene.