Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease without appropriate cure. One of the main reasons for the lack of a proper pharmacotherapy in ALS is the narrow knowledge on the molecular causes of the disease. In this respect, the identification of dysfunctional pathways in ALS is now considered a critical medical need. Among the causative factors involved in ALS, Ca^2 + dysregulation is one of the most important pathogenetic mechanisms of the disease. Of note, Ca^2 + dysfunction may induce, directly or indirectly, motor neuron degeneration and loss. Interestingly, both familial (fALS) and sporadic ALS (sALS) share the progressive dysregulation of Ca^2 + homeostasis as a common noxious mechanism. Mechanicistically, Ca^2 + dysfunction involves both plasma membrane and intracellular mechanisms, including AMPA receptor (AMPAR)-mediated excitotoxicity, voltage-gated Ca^2 + channels (VGCCs) and Ca^2 + transporter dysregulation, endoplasmic reticulum (ER) Ca^2 + deregulation, mitochondria-associated ER membranes (MAMs) dysfunction, lysosomal Ca^2 + leak, etc. Here, a comprehensive analysis of the main pathways involved in the dysregulation of Ca^2 + homeostasis has been reported with the aim to focus the attention on new putative druggable targets.

肌萎缩侧索硬化症 (ALS) 是一种毁灭性的神经退行性疾病，没有适当的治疗方法。在 ALS 中缺乏适当的药物治疗的主要原因之一是对该疾病的分子原因的了解狭窄。在这方面，识别 ALS 中功能失调的通路现在被认为是一项关键的医疗需求。在与ALS相关的致病因素中，Ca ^{2  +}失调是该疾病最重要的发病机制之一。值得注意的是，Ca ^{2  +}功能障碍可能直接或间接地诱发运动神经元退化和丧失。有趣的是，家族性 (fALS) 和散发性 ALS (sALS) 都存在进行性 Ca ^{2  +失调}稳态是一种常见的有害机制。从机制上讲，Ca ^{2  +}功能障碍涉及质膜和细胞内机制，包括 AMPA 受体 (AMPAR) 介导的兴奋性毒性、电压门控 Ca ^{2  +}通道 (VGCC) 和 Ca ^{2  +}转运蛋白失调、内质网 (ER) Ca ^{2  +}失调、线粒体相关ER膜（MAMs）功能障碍、溶酶体Ca ^{2  +}渗漏等。这里综合分析涉及Ca ^{2  +失调的主要途径}已经报道了体内平衡，旨在将注意力集中在新的假定药物靶点上。