Ca2+ dysregulation in the pathogenesis of amyotrophic lateral sclerosis

Abstract

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.

Keywords: ALS; ALS preclinical models; Ca(2+) dysregulation; ER stress; Excitotoxicity; Organellar Ca(2+).