Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death
Brain Research ReviewsPublished 1 December 1997
J.S. Bains, Christopher A. Shaw
Citations718
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TL;DR
A GSH-depletion model of neurodegenerative disorders is provided, experimental verifications of this model are suggested, and potential therapeutic approaches for preventing or halting these diseases are proposed.
Abstract
Oxidative stress has been implicated in both normal aging and in various neurodegenerative disorders and may be a common mechanism underlying various forms of cell death including necrosis, apoptosis, and excitotoxicity. In this review, we develop the hypothesis that oxidative stress-mediated neuronal loss may be initiated by a decline in the antioxidant molecule glutathione (GSH). GSH plays multiple roles in the nervous system including free radical scavenger, redox modulator of ionotropic receptor activity, and possible neurotransmitter. GSH depletion can enhance oxidative stress and may also increase the levels of excitotoxic molecules; both types of action can initiate cell death in distinct neuronal populations. Evidence for a role of oxidative stress and diminished GSH status is presented for Lou Gehrig's disease (ALS), Parkinson's disease, and Alzheimer's disease. Potential links to the Guamanian variant of these diseases (ALS-PD complex) are discussed. In context to the above, we provide a GSH-depletion model of neurodegenerative disorders, suggest experimental verifications of this model, and propose potential therapeutic approaches for preventing or halting these diseases.
Keywords
MedicineBiochemistry, Genetics and Molecular Biology
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Biochemical and Biophysical Research Communicationsβ-Amyloid Peptide Free Radical Fragments Initiate Synaptosomal Lipoperoxidation in a Sequence-Specific Fashion: Implications to Alzheimer′s Disease
404 Citations1994D. Allan Butterfield, K. Hensley +3 more
It is reported that Aβ(25-35) is a potent lipoperoxidation initiator, as inferred from peptide-mediated reduction of nitroxyl stearate spin labels bound to rodent neocortical synaptosomal membranes, a "molecular shrapnel" model of neuronal membrane damage in Alzheimer′s disease.
Proceedings of the National Academy of SciencesDopamine turnover and glutathione oxidation: implications for Parkinson disease.
397 Citations1989Mary Beth Spina, G. Cohen
Observations confirm that a selective increase in neurotransmitter turnover within nigrostriatal nerve terminals can evoke a change in cellular redox status and suggest that an oxidative stress may play a role in the natural history of Parkinson disease.
Proceedings of the National Academy of SciencesAmyloid peptides are toxic via a common oxidative mechanism.
382 Citations1995David Schubert, Christian Behl +5 more
It is shown here that the protein components of other human amyloidoses, including amylin, calcitonin, and atrial natriuretic peptide, are all toxic to clonal and primary cells.
Annals of NeurologyAn introduction to the free radical hypothesis in Parkinson's disease
381 Citations1992C. Warren Olanow
This data indicates that in Parkinson's disease the environment within the substantia nigra is conducive to the formation of cytotoxic free radicals and cell degeneration, and dopamine neurons may be particularly vulnerable because of the oxidative metabolism of dopamine.
Proceedings of the National Academy of SciencesOxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.
366 Citations1995O. Schweers, Eva‐Maria Mandelkow +2 more
The in vitro assembly of recombinant tau protein and constructs derived from it into PHFs and the synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics imply that the redox potential in the neuron is crucial for PHF assembly, independently or in addition to pathological phosphorylation reactions.
Neurobiology of AgingAre reactive oxygen species involved in Alzheimer's disease?
363 Citations1995Gianni Benzi
This review examines the possibility of oxidative stress, meaning an imbalance between the formation and spread of reactive oxygen species (ROS) and the antioxidant defenses, and the pro-aggregating effect of ROS on beta/A4 protein and the C-terminal fragment of amyloid precursor (A4CT).
Neuroscience LettersIdiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients
361 Citations1986Thomas L. Perry, V. Wee Yong
Since total GSH is consumed only by conjugation in detoxification processes, nigral GSH deficiency in PD patients implies continued local presence of a possible causative neurotoxin up to the time of death.
Annals of NeurologyImpact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa
359 Citations1996Parkinson Study Group
It is concluded that prior treatment with deprenyl or tocopherol did not reduce the occurrence of subsequent levodopa-associated adverse effects in this population of patients with Parkinson's disease.
Neuroscience4-Hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes
353 Citations1997Jeffrey N. Keller, Robert J. Mark +6 more
Evidence is provided that 4-hydroxynonenal, an aldehydic product of lipid peroxidation, mediates oxidation-induced impairment of glutamate transport and mitochondrial function in synapses and plays important roles in oxidative impairment of synaptic functions that would be expected to promote excitotoxic cascades.
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