INTRACELLULAR CALCIUM PARALLELS MOTONEURON DEGENERATION IN SOD-1 MUTANT MICE

Transgenic mice with Cu,Zn superoxide dismutase (SOD-1) mutations prov ide a unique model to examine altered Ca homeostasis in selectively vu lnerable and resistant motoneurons. In degenerating spinal motoneurons of G93 A SOD-1 mice, developing vacuoles were filled with calcium, wh ile calcium was gradually depleted from the cytoplasm and intact mitoc hondria. In oculomotor neurons, no degenerative changes, vacuolization , or increased calcium were noted. Motor axon terminals of interosseus muscle gradually degenerated and intracellular calcium was depleted. Oculomotor terminals of mutant SOD-1 mice were smaller and exhibited n o degenerative changes, but did exhibit unique membrane-enclosed organ elles containing calcium. Spinal motoneurons of SOD-1 mice were shown to have fewer calcium binding proteins, such as parvalbumin, compared with oculomotor neurons. These data suggest that the SOD-1 mutation is associated with impaired calcium homeostasis in motoneurons in vivo, with increased likelihood of degeneration associated with higher level s of intracellular calcium and lower to absent levels of calbindin-D28 K and/or parvalbumin, and decreased likelihood of degeneration associa ted with minimally changed calcium and ample calbindin-D28K and/or par valbumin.