Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons
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TLDR
It is found that glutamate induces far greater reactive oxygen species (ROS) generation in cultured motor neurons than in other spinal neurons, and the ROS seem to be able to leave the motor neurons and induce oxidation and disruption of glutamate uptake in neighboring astrocytes.Abstract:
Observations of elevated CSF glutamate in amyotrophic lateral sclerosis (ALS), together with findings that motor neurons are selectively vulnerable to glutamate receptor-mediated ("excitotoxic") injury, support an excitotoxic contribution to the motor neuron loss in the disease. However, the basis of the apparent loss of astrocytic glutamate transport capacity in affected areas of motor cortex and spinal cord, which probably underlies the extracellular glutamate elevations, is unexplained. Here, we find that glutamate induces far greater reactive oxygen species (ROS) generation in cultured motor neurons than in other spinal neurons. In addition, we found that the ROS seem to be able to leave the motor neurons and induce oxidation and disruption of glutamate uptake in neighboring astrocytes. Correspondingly, in a transgenic mouse model of ALS, protein oxidation was increased in regions immediately surrounding motor neurons. These results provide a mechanism that can account for the localized loss of glial glutamate transport seen in the disease. Furthermore, the observations lend support for a feedforward model involving reciprocal interactions between motor neurons and glia, which may prove useful in understanding ALS pathogenesis.read more
Citations
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Astrocyte dysfunction in neurological disorders: a molecular perspective
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Mitochondria in health and disease: perspectives on a new mitochondrial biology.
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Oxidative stress in ALS: key role in motor neuron injury and therapeutic target.
Siân C. Barber,Pamela J. Shaw +1 more
TL;DR: There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and the trials of a variety of antioxidants as potential therapies for ALS are reviewed.
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Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity.
Gabriel Olmos,Jerònia Lladó +1 more
TL;DR: This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF-α links the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS).
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Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target
TL;DR: The evidence implicating oxidative stress in ALS pathogenesis is reviewed, how oxidative stress may affect and be affected by other proposed mechanisms of neurodegeneration, and the trials of various anti-oxidants as potential therapies for ALS are reviewed.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
Mark E. Gurney,Haifeng Pu,Arlene Y. Chiu,Mauro C. Dal Canto,Cynthia Y. Polchow,Denise D. Alexander,Jan Caliendo,Afif Hentati,Young W. Kwon,Han Xiang Deng,W. Chen,Ping Zhai,Robert L. Sufit,Teepu Siddique +13 more
TL;DR: In this article, the authors found that mutations of human Cu,Zn superoxide dismutase (SOD) contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS).
Journal ArticleDOI
Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate
Jeffrey D. Rothstein,Margaret Dykes-Hoberg,Carlos A. Pardo,Lynn A. Bristol,Lin Jin,Ralph W. Kuncl,Yoshikatsu Kanai,Matthias A. Hediger,Yanfeng Wang,Jerry P Schielke,Devin Franklin Welty +10 more
TL;DR: It is suggested that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.
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Epilepsy and Exacerbation of Brain Injury in Mice Lacking the Glutamate Transporter GLT-1
Kohichi Tanaka,Kei Watase,Toshiya Manabe,Keiko Yamada,Masahiko Watanabe,Katsunobu Takahashi,Hisayuki Iwama,Toru Nishikawa,Nobutsune Ichihara,Tateki Kikuchi,Shigeru Okuyama,Naoya Kawashima,Seiji Hori,Misato Takimoto,Keiji Wada +14 more
TL;DR: Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury, which can be attributed to elevated levels of residual glutamate in the brains of these mice.
Journal ArticleDOI
NMDA-dependent superoxide production and neurotoxicity
TL;DR: It is reported that O·- 2 is produced upon NMDA receptor stimulation in cultured cerebellar granule cells and the nitrone DMPO (5,5-dimethyl pyrroline 1-oxide), used as a spin trap, is more efficient than the nitric oxide synthase inhibitor, L-N G -nitroarginine, in reducing NMDA-induced neuronal death in these cultures.