Figure 4.

The interrelationship between autophagy and other pathogenic mechanisms in ALS. Dysfunction of autophagy, specifically, aggrephagy (aggregate-specific autophagy), mitophagy (aggregate-specific autophagy), and reticulophagy (ER-specific autophagy) leads to the build-up of protein aggregates, damaged mitochondria, and ER stress, respectively. Thus, inducing reactive oxygen species (ROS) production, which persistently builds up in ALS to inhibit autophagy, stabilises aggregates and induces inflammation and excitotoxicity. Excitotoxicity over-activates neurons, resulting in cytoplasmic and mitochondrial calcium augmentation and hence further mitochondrial damage. As a result of these impairments, cells undergo apoptosis and death.