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.