The ER under rapid fire

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to selective death of upper and lower motoneurons. Clinically, the ALS syndrome is linked to pathogenic mutations in superoxide dismutase 1 (SOD1), though actual molecular mechanisms remain ill understood. Two papers recently published in Cell Stem Cell and Cell Reports employ syngenic, iPSC-derived cell lines of one of the most severe SOD1 mutations to report mitochondrial and ER stress as causal for perturbed electrical activity in ALS neurons (Kiskinis et al, 2014; Wainger et al, 2014).

Figure 1. Vicious cycle of ER stress and hyperexcitability in SOD1 A4V motoneurons

(A) Generation of isogenic SOD1 A4V and wild-type human motoneurons: iPSCs from skin fibroblast of a SOD1 A4V ALS-patient were generated and further differentiated into motoneurons. The mutation was repaired in the iPSCs by ZFN-mediated genome editing and the SOD1 A4V and its isogenic control motoneuron line analyzed. (B) Hypothetic model of SOD1 A4V pathogenesis: SOD1 A4V mutation enhances UPR and induces ER stress. ER stress leads to hyperexcitability and hyperactivity of the motoneurons which in turn activates UPR resulting in a vicious cycle causing neuronal death. This cycle can be broken pharmacologically by inhibition of ER stress with salubrinal or activation of depolarizing Kv7 channels with retigabine and genetically by isogenic repair of the SOD1 mutation.