Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis

Current research evidence suggests that genetic factors, oxidative stress a nd glutamatergic toxicity, with damage to critical target proteins and orga nelles, may be important contributory factors to motor neuron injury in amy otrophic lateral sclerosis (ALS). Various molecular and neurochemical featu res of human motor neurons may render this cell group differentially vulner able to such insults. Motor neurons are large cells with long axonal proces ses which lead to requirements for a high level of mitochondrial activity a nd a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low e xpression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor a ctivation. Motor neurons also have a high perisomatic expression of the glu tamate transporter protein EAAT2 and a very high expression of the cytosoli c free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which ma y render this cell group vulnerable in the face of genetic or post-translat ional alterations interfering with the function of these proteins. More det ailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective th erapies for the benefit of patients afflicted by ALS.