[ALS and excitatory amino acid].
AMPA receptor, one of ionotropic glutamate receptors, has been proposed to play a critical role to initiate the neuronal death cascade in motor neuron disease by an increase of Ca2+ influx. There are at least two mechanisms to increase Ca2+ influx through Ca2+-permiable AMPA receptor: a decrease of RNA editing efficacy at the GluR2 Q/R site and a decrease of GluR2 level relative to AMPA receptor subunits. Deficient RNA editing of the AMPA receptor subunit GluR2 at the Q/R site is a primary cause of neuronal death and recently has been reported to be a tightly linked etiological cause of motor neuron death in sporadic amyotrophic lateral sclerosis (ALS). On the other hand, relative low GluR2 level among AMPA receptor subunits seems to increase Ca2+ permeability of motor neurons in familial ALS (ALS1) linked to mutated cupper-zinc superoxide dismutase gene (SOD1). AMPA receptor-mediated mechanism does not seem to play any role in death of motor neurons in X-linked spinal and bulbar muscular atrophy (SBMA). From the molecular pathomechanism of sporadic ALS and ALS1, drugs which increase RNA editing efficacy at the GluR2 Q/R site could be a potent therapy for sporadic ALS, while AMPA receptor antagonists could prevent deterioration from ALS1.
Aizawa
Hitoshi
H
Division of Neurology, Department of Internal Medicine, Asahik-awa Medical College, 2-1-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
Kwak
Shin
S
D000243:Adenosine Deaminase; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000628:therapy*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D006801:Humans; D009046:Motor Neurons; D009154:Mutation; D017393:RNA Editing; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA / Q000235:genetics* / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium