Endoplasmic Reticulum Stress and Protein Misfolding in Amyotrophic Lateral Sclerosis

The accumulation of ubiquitinated protein inclusions is a hallmark of amyotrophic laterals sclerosis (ALS), a rapidly progressing fatal neurodegenerative disease primarily affecting motor neurons. However, the exact cause of motor neuron death in ALS remains unclear. The unfolded protein response (UPR) is a homeostatic mechanism, which is activated in response to endoplasmic reticulum (ER) stress caused by unfolded or misfolded proteins within the ER lumen. The UPR activates three signalling pathways that lead to an up-regulation of protein chaperones and a block in general protein synthesis. However, chronic UPR activation promotes cell death via apoptosis. Here we review evidence from human patients and experimental models implicating ER-stress induced cell death in ALS. Recently, activation of all three UPR transduction pathways was shown in spinal cords of patients affected by ALS, including up-regulation of protein disulfide isomerase (PDI), an important ER chaperone, and activation of the ER stress-specific apoptotic factor caspase-4. Similarly, expression of mutant superoxide dismutase 1 (SOD1) proteins, which cause 20% of familial ALS cases, leads to activation of the UPR in neuronal cell culture and transgenic mutant SOD1 mice, which are the most widely accepted animal model of disease. Microsomal localisation and SNARE complex-regulated secretion of SOD1 implies entry into the ER-Golgi secretory pathway, and we discuss the disruptive effects of mutant SOD1 on the Golgi apparatus and general protein export. Importantly, the links between ER stress and other pathways implicated in ALS, including autophagy, oxidative stress and the ubiquitin-proteasome system, are becoming increasingly recognised, suggesting that ER stress is a central mechanism in disease. These observations suggest novel potential therapeutic targets for ALS.