Calcium: the Darth Vader of ALS

Motor neuron dysfunction and loss in amyotrophic lateral sclerosis (ALs) ha ve been attributed to several different mechanisms, including increased int racellular calcium, glutamate excitotoxicity, oxidative stress and free rad ical damage, mitochondrial dysfunction, and neurofilament aggregation and d ysfunction of transport mechanisms. These alterations are not mutually excl usive, and increased calcium could be a common denominator. Furthermore, th e selective vulnerability of spinal motor neurons and the relative sparing of eye motor neurons represent striking features of both sporadic and famil ial ALS. Here we review the evidence that calcium homeostasis is altered in ALs, and that low levels of the calcium binding proteins parvalbumin and c albindin-D-28K contribute to selective vulnerability by decreasing the abil ity of motor neurons to handle an increased calcium load, with call injury and death as the consequence.