Cu/Zn-superoxide dismutase (GLY93→ALA) mutation alters AMPA receptor subunit expression and function and potentiates kainate-mediated toxicity in motor neurons in culture

• Published in: Neurobiology of disease Vol. 15; no. 2; pp. 340 - 350
• Main Authors: Spalloni, Alida, Albo, Federica, Ferrari, Francesca, Mercuri, Nicola, Bernardi, Giorgio, Zona, Cristina, Longone, Patrizia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2004; Elsevier
• Subjects: Alanine - genetics; Alanine - metabolism; ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Animals; Cells, Cultured; Drug Resistance - genetics; Excitotoxicity; Fetus; Genetic Predisposition to Disease - genetics; Glutamate receptors; Glycine - genetics; Glycine - metabolism; Kainic Acid - pharmacology; Membrane Potentials - drug effects; Membrane Potentials - genetics; Mice; Mice, Transgenic; Motor neuron; Motor Neurons - drug effects; Motor Neurons - enzymology; Motor Neurons - pathology; Mutation - genetics; Neurotoxins - pharmacology; Protein Subunits - drug effects; Protein Subunits - genetics; Protein Subunits - metabolism; Receptors, AMPA - drug effects; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; RNA, Messenger - metabolism; scRT-PCR; Selective vulnerability; Superoxide Dismutase - genetics; Superoxide dismutase-1; Synaptic Transmission - drug effects; Synaptic Transmission - genetics; Glutamate receptors; G93A; Superoxide dismutase-1; ALS; CTZ; Amyotrophic lateral sclerosis; Motor neuron; AMPAR; SOD1; Excitotoxicity; scRT-PCR; Selective vulnerability; NMDA
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2003.11.012

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.