Calcium Dyshomeostasis and Lysosomal Ca(2+) Dysfunction in Amyotrophic Lateral Sclerosis

Recent findings in the understanding of amyotrophic lateral sclerosis (ALS) revealed that alteration in calcium (Ca(2+)) homeostasis may largely contribute to motor neuron demise. A large part of these alterations is due to dysfunctional Ca(2+)-storing organelles, including the endoplasmic reticulum (ER) and mitochondria. Very recently, lysosomal Ca(2+) dysfunction has emerged as an important pathological change leading to neuronal loss in ALS. Remarkably, the Ca(2+)-storing organelles are interacting with each other at specialized domains controlling mitochondrial dynamics, ER/lysosomal function, and autophagy. This occurs as a result of interaction between specific ionic channels and Ca(2+)-dependent proteins located in each structure. Therefore, the dysregulation of these ionic mechanisms could be considered as a key element in the neurodegenerative process. This review will focus on the possible role of lysosomal Ca(2+) dysfunction in the pathogenesis of several neurodegenerative diseases, including ALS and shed light on the possibility that specific lysosomal Ca(2+) channels might represent new promising targets for preventing or at least delaying neurodegeneration in ALS.