Endoplasmic Reticulum (ER) Stress in Amyotrophic Lateral Sclerosis (ALS)

Abstract

There have been considerable advances in understanding amyotrophic lateral sclerosis/motor neuron disease (ALS), particularly within the last 5 years with the identification of mutations in 4 key genes, TARDBP, FUS, VCP and VAPB that cause familial ALS. The strong association of TDP-43 with ubiquitinated protein aggregates in motor neurons, a hallmark of ALS in sporadic cases of ALS, clearly demonstrates the importance of these findings for understanding the pathology of sporadic cases. All of these genes are known to be involved in multiple cellular pathways but the key features that underpin ALS remain to be elucidated. What is known is that these causal genes result in a severe perturbation in the removal of mis-folded proteins with the accumulation of aggregated proteins. This may in part be due to protein degradation and mislocation and in some instances, it may be due to a direct effect on endogenous components of cellular protein control, the unfolded protein response (UPR) which operates within the endoplasmic reticulum (ER) and protein degradation pathways such as the ubiquitin proteasomal system (UPS) and early and late autophagy. Mutations in Vesicle associated protein-associated protein B (VAPB) and Valosin containing protein (VCP) cause familial Amyotrophic Lateral Sclerosis (FALS), which strongly indicates the importance of the prosurvival properties of these proteins in endoplasmic reticulum (ER) stress responses. The main components of ER stress and associated pathways include the unfolded protein response (UPR), ER–associated degradation (ERAD), the ubiquitin-proteasome system (UPS) and autophagy, all of which are known to be activated in ALS.