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Adaptation to G93Asuperoxide dismutase 1 in a motor neuron cell line
model of amyotrophic lateral sclerosis: The role of glutathione
Tartari S, D'Alessandro G, Babetto E, Rizzardini M, Conforti L, Cantoni L.
FEBS J. 2009 May;276(10):2861-74.
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version of this abstract
Motor neuron degeneration in
amyotrophic lateral sclerosis involves oxidative damage. Glutathione
(GSH) is critical as an antioxidant and a redox modulator. We used a
motor neuronal cell line (NSC-34) to investigate whether wild-type and
familial amyotrophic lateral sclerosis-linked G93A mutant Cu,Zn
superoxide dismutase (wt/G93ASOD1) modified the GSH pool and glutamate
cysteine ligase (GCL), the rate-limiting enzyme for GSH synthesis. We
studied the effect of various G93ASOD1 levels and exposure times. Mutant
Cu,Zn superoxide dismutase induced an adaptive process involving the
upregulation of GSH synthesis, even at very low expression levels.
However, cells with a high level of G93ASOD1 cultured for 10 weeks
showed GSH depletion and a decrease in expression of the modulatory
subunit of GCL. These cells also had lower levels of GSH and GCL
activity was not induced after treatment with the pro-oxidant
tert-butylhydroquinone. Cells with a low level of G93ASOD1 maintained
higher GSH levels and GCL activity, showing that the exposure time and
the level of the mutant protein modulate GSH synthesis. We conclude that
failure of the regulation of the GSH pathway caused by G93ASOD1 may
contribute to motor neuron vulnerability and we identify this pathway as
a target for therapeutic intervention.
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