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.
