Ca2 + dysregulation in the pathogenesis of amyotrophic lateral sclerosis

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, Ca2 + dysregulation is one of the most important pathogenetic mechanisms of the disease. Of note, Ca2 + dysfunction may induce, directly or indirectly, motor neuron degeneration and loss. Interestingly, both familial (fALS) and sporadic ALS (sALS) share the progressive dysregulation of Ca2 + homeostasis as a common noxious mechanism. Mechanicistically, Ca2 + dysfunction involves both plasma membrane and intracellular mechanisms, including AMPA receptor (AMPAR)-mediated excitotoxicity, voltage-gated Ca2 + channels (VGCCs) and Ca2 + transporter dysregulation, endoplasmic reticulum (ER) Ca2 + deregulation, mitochondria-associated ER membranes (MAMs) dysfunction, lysosomal Ca2 + leak, etc. Here, a comprehensive analysis of the main pathways involved in the dysregulation of Ca2 + homeostasis has been reported with the aim to focus the attention on new putative druggable targets.