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The Journal of Neuroscience, October 1, 2002, 22(19):8402-8410

Thioltransferase (Glutaredoxin) Mediates Recovery of Motor Neurons from Excitotoxic Mitochondrial Injury

Rajappa S. Kenchappa1, 2, Latha Diwakar1, Michael R. Boyd3, and Vijayalakshmi Ravindranath1, 2

1 Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore 560 029, India, 2 National Brain Research Centre, Gurgaon 122001, India, and 3 Cancer Research Institute, College of Medicine, Mobile, Alabama 36688

Mitochondrial dysfunction involving electron transport components is implicated in the pathogenesis of several neurodegenerative disorders and is a critical event in excitotoxicity. Excitatory amino acid L-beta -N-oxalylamino-L-alanine (L-BOAA), causes progressive corticospinal neurodegeneration in humans. In mice, L-BOAA triggers glutathione loss and protein thiol oxidation that disrupts mitochondrial complex I selectively in motor cortex and lumbosacral cord, the regions affected in humans. We examined the factors regulating postinjury recovery of complex I in CNS regions after a single dose of L-BOAA. The expression of thioltransferase (glutaredoxin), a protein disulfide oxidoreductase regulated through AP1 transcription factor was upregulated within 30 min of L-BOAA administration, providing the first evidence for functional regulation of thioltransferase during restoration of mitochondrial function. Regeneration of complex I activity in motor cortex was concurrent with increase in thioltransferase protein and activity, 1 hr after the excitotoxic insult. Pretreatment with alpha -lipoic acid, a thiol delivery agent that protects motor neurons from L-BOAA-mediated toxicity prevented the upregulation of thioltransferase and AP1 activation, presumably by maintaining thiol homeostasis. Downregulation of thioltransferase using antisense oligonucleotides prevented the recovery of complex I in motor cortex and exacerbated the mitochondrial dysfunction in lumbosacral cord, providing support for the critical role for thioltransferase in maintenance of mitochondrial function in the CNS.

Key words: excitatory amino acid; glutaredoxin; mitochondria; motor neuron disease; glutathione; brain; complex I; oxidative stress

Copyright © 2002 Society for Neuroscience  0270-6474/02/22198402-09$05.00/0




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