Excitotoxicity and genetics of amyotrophic lateral sclerosis: effects of intracellular calcium accumulation on proteins encoded by the major genes underlying the disease

The aetiology of Amyotrophic Lateral Sclerosis (ALS), a fatal and incurable disease caused by motor neuron degeneration, is still poorly understood. The discovery of genetic forms of ALS helped to shed light on the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is one of the processes strongly suspected to play a role in motor neuron degeneration in ALS. This process consists in neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and excitotoxicity. In detail, the profile of eight proteins (TDP-43, C9ORF72, p62/SQSTM1, matrin3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a significant decrease in the levels of TDP-43, C9ORF72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in p62/SQSTM1. These events are associated to the proteolytic action of two proteases, calpains and caspases, as well as to the activation of autophagy, a process responsible for the degradation and recycling of cytoplasmic components. Interestingly, Ca2+ appears to both favour and hinder autophagy. The discovery of when Ca2+ levels become toxic for the cell, as well as understanding why the physiological processes of calpain proteolysis and autophagy become pathological, may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.