Department of Neuroscience, ALS Centre, "Rita Levi Montalcini", University of Turin, Via Cherasco 15, 10126, Turin, Italy.
Neurology Unit 1, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Via Cherasco 15, 10126, Turin, Italy.
Sci Rep. 2022 Jan 10;12(1):395. doi: 10.1038/s41598-021-04267-8.
The aetiology of Amyotrophic Lateral Sclerosis (ALS) is still poorly understood. The discovery of genetic forms of ALS pointed out the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is strongly suspected to play a role in ALS pathogenesis. Excitotoxicity is defined as neuron damage due to excessive intake of calcium ions (Ca) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and intracellular Ca accumulation. In detail, the profile of eight proteins (TDP-43, C9orf72, p62/sequestosome-1, matrin-3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca. Intracellular Ca accumulation causes a decrease in the levels of TDP-43, C9orf72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in those of p62/sequestosome-1. These events are associated with the proteolytic action of two proteases, calpains and caspases, as well as with the activation of autophagy. Interestingly, Ca appears to both favour and hinder autophagy. Understanding how and why calpain-mediated proteolysis and autophagy, which are physiological processes, become pathological may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.
肌萎缩侧索硬化症（ALS）的病因仍知之甚少。遗传性 ALS 的发现指出了这种病理学的潜在机制，但也表明这些机制是多么复杂。兴奋性毒性强烈怀疑在 ALS 的发病机制中起作用。兴奋性毒性被定义为细胞内钙离子（Ca）过度摄取导致的神经元损伤。本研究旨在寻找与 ALS 相关的最相关基因编码的蛋白质与细胞内 Ca 积累之间的关系。具体来说，在三种不同的细胞类型中分析了八种蛋白质（TDP-43、C9orf72、p62/自噬体-1、matrin-3、VCP、FUS、SOD1 和肌动蛋白-1）的蛋白谱，以诱导它们增加细胞质中的 Ca 含量。细胞内 Ca 积累导致 TDP-43、C9orf72、matrin3、VCP、FUS、SOD1 和肌动蛋白-1的水平降低，而 p62/自噬体-1的水平升高。这些事件与两种蛋白酶（钙蛋白酶和半胱天冬酶）的蛋白水解作用以及自噬的激活有关。有趣的是，Ca 似乎既促进又阻碍自噬。了解钙蛋白酶介导的蛋白水解和自噬（这是两种生理过程）如何以及为何变得病理性，可能阐明导致 ALS 的机制，并有助于发现新的治疗靶点。
