Coupling ER stress to motor neuron degeneration in ALS

Misfolded and aggregated species of mutant superoxide dismutase I (SOD I) are associated with one form of inherited amyotrophic lateral sclerosis (ALS), however their causal relationship to motor neuron death remains obscure. Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen initiates intracellular stress signalling pathways co-ordinating the unfolded protein response (UPR). Although initially protective and homeostatic, chronic activation of the UPR promotes cell death via apoptotic mechanisms. Here, we review recent evidence from patients and experimental models of ALS implicating ER stress-induced cell death in motor neuron disease. Mutant SODI preferentially upregulates and interacts with the ER resident chaperones protein disulfide isomerase {PDI) and immunoglobulin binding protein in spinal cords of transgenic ALS rodents. Furthermore, PDI modulates the aggregation of SOD I mutants which is mediated by disulfide crosslinkage between monomers. Next, markers for all three ER stress transduction pathways are detectable in ALS tissues. Finally, apoptotic factors such as caspase-12 are active in spinal cords of transgenic ALS mice indicative of ER stress. Microsomal localisation of mutant SOD I also implies its entry into the secretory pathway and the subsequent disruptive effects of secreted SOD I mutants on the Golgi complex and protein export are discussed. These findings suggest that UPR activation provides one molecular link between mutant SODI aggregation and motor neuron degeneration. Thus, ER stress-induced apoptosis may be a previously unconsidered important player in ALS pathogenesis with application for therapeutic targeting.