Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis.
Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.
Shaw
P J
PJ
Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK. Pamela.Shaw@ncl.ac.uk
Eggett
C J
CJ
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003599:Cytoskeleton; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D009046:Motor Neurons / Q000473:pathology* / Q000502:physiology; D009410:Nerve Degeneration; D017354:Point Mutation; D017470:Receptors, Glutamate / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D002135:Calcium-Binding Proteins; D017470:Receptors, Glutamate; C000606290:SOD1 protein, human; D018698:Glutamic Acid; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1