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The Journal of Neuroscience, December 1, 1998, 18(23):9673-9684
Glutamate Potentiates the Toxicity of Mutant Cu/Zn-Superoxide
Dismutase in Motor Neurons by Postsynaptic Calcium-Dependent
Mechanisms
Josée
Roy1,
Sandra
Minotti1,
Lichun
Dong2,
Denise A.
Figlewicz2, 3, and
Heather D.
Durham1
1 Montreal Neurological Institute and Department of
Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
H3A 2B4, and Departments of 2 Neurology and
3 Neurobiology and Anatomy, University of Rochester,
University of Rochester Medical Center, Rochester, New York 14642
Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are
responsible for a subset of familial cases of amyotrophic lateral sclerosis. Using a primary culture model, we have demonstrated that normally nontoxic glutamatergic input, particularly via
calcium-permeable AMPA/kainate receptors, is a major factor in the
vulnerability of motor neurons to the toxicity of SOD-1 mutants.
Wild-type and mutant (G41R, G93A, or N139K) human SOD-1 were expressed
in motor neurons of dissociated cultures of murine spinal cord by
intranuclear microinjection of plasmid expression vector. Both a
general antagonist of AMPA/kainate receptors (CNQX) and a specific
antagonist of calcium-permeable AMPA receptors (joro spider toxin)
reduced formation of SOD-1 proteinaceous aggregates and prevented death
of motor neurons expressing SOD-1 mutants. Partial protection was
obtained by treatment with nifedipine, implicating
Ca2+ entry through voltage-gated calcium channels as
well as glutamate receptors in potentiating the toxicity of mutant
SOD-1 in motor neurons. Dramatic neuroprotection was obtained by
coexpressing the calcium-binding protein calbindin-D28k but not by
increasing intracellular glutathione levels or treatment with the free
radical spin trap agent, N-tert-butyl- -phenylnitrone.
Thus, generalized oxidative stress could have contributed in only a
minor way to death of motor neurons expressing the mutant SOD-1. These
studies demonstrated that the toxicity of these mutants is
calcium-dependent and provide direct evidence that calcium entry during
neurotransmission, coupled with deficiency of cytosolic calcium-binding
proteins, is a major factor in the preferential vulnerability of motor
neurons to disease.
Key words:
amyotrophic lateral sclerosis; ALS; superoxide
dismutase-1; neurotoxicity; motor neuron; culture model; excitotoxicity; glutamate receptors; calbindin; calcium-binding
proteins; glutathione; selective vulnerability; oxidative stress
Copyright © 1998 Society for Neuroscience 0270-6474/98/18239673-12$05.00/0
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