Cu/Zn-superoxide dismutase (GLY93-->ALA) mutation alters AMPA receptor subunit expression and function and potentiates kainate-mediated toxicity in motor neurons in culture.
The cause of the selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) remains a mystery. One potential pathogenic mechanism is excitotoxicity due to disturbances of glutamatergic neurotransmission, particularly via AMPA-sensitive glutamate receptors. We report here that motor neurons from a familial ALS-linked superoxide dismutase (SOD1) mutant G93A mouse show an higher susceptibility to kainate-induced excitotoxicity. Moreover, they expressed GluR(3) and GluR(4) mRNA at detectable levels more frequently, with a modified electrophysiology when compared with control and wild-type SOD1 motor neurons. Thus, the SOD1 G93A mutation causes changes in the AMPA-receptor expression and function, as well as a susceptibility to kainate-mediated excitotoxicity, which may promote the motor neuron degeneration seen in ALS.
Spalloni
Alida
A
Fondazione Santa Lucia IRCCS, 00179 Rome, Italy.
Albo
Federica
F
Ferrari
Francesca
F
Mercuri
Nicola
N
Bernardi
Giorgio
G
Zona
Cristina
C
Longone
Patrizia
P
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D004351:Drug Resistance / Q000235:genetics; D005333:Fetus; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009498:Neurotoxins / Q000494:pharmacology; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
D009498:Neurotoxins; D021122:Protein Subunits; D012333:RNA, Messenger; D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3; C104724:glutamate receptor ionotropic, AMPA 4; D013482:Superoxide Dismutase; D000409:Alanine; D007608:Kainic Acid; D005998:Glycine