Protein modification by the lipid peroxidation product 4‐hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients

We report increased modification of proteins by 4‐hydroxynoneal (HNE), a product of membrane lipid peroxidation, in the lumbar spinal cord of sporadic amyotrophic lateral sclerosis (ALS) patients versus that of neurologically normal controls. By immunohistochemistry, HNE‐protein modification was detected in ventral horn motor neurons, and immunoprecipitation analysis revealed that one of the proteins modified by HNE was the astrocytic glutamate transporter EAAT2. Given that the function of proteins modified by HNE can be severely compromised as previously demonstrated for glutamate transporters in cortical synaptosome preparatations, our findings suggest a scenario in which oxidative stress leads to the production of HNE, impairment of gluatmate transport, and excitotoxic motor neuron degeneration in ALS.

[1]  A. Imperato,et al.  Glutamate uptake is decreased tardively in the spinal cord of FALS mice , 1998, Neuroreport.

[2]  M. Mattson,et al.  4‐hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes , 1998, Glia.

[3]  J. B. Hutchins,et al.  Bcl‐2 Protects Isolated Plasma and Mitochondrial Membranes Against Lipid Peroxidation Induced by Hydrogen Peroxide and Amyloid β‐Peptide , 1998, Journal of neurochemistry.

[4]  W. D. Ehmann,et al.  Elevated 4-Hydroxynonenal in Ventricular Fluid in Alzheimer’s Disease , 1997, Neurobiology of Aging.

[5]  M. Mattson,et al.  4-Hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes , 1997, Neuroscience.

[6]  M. Dubois‐Dauphin,et al.  Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. , 1997, Science.

[7]  D. Price,et al.  Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Mattson,et al.  Impairment of Glucose and Glutamate Transport and Induction of Mitochondrial Oxidative Stress and Dysfunction in Synaptosomes by Amyloid β‐Peptide: Role of the Lipid Peroxidation Product 4‐Hydroxynonenal , 1997, Journal of neurochemistry.

[9]  Hiroshi Mitsumoto,et al.  Diagnosis and progression of ALS , 1997, Neurology.

[10]  H. Horvitz,et al.  Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis , 1997, Annals of neurology.

[11]  M. Mattson,et al.  A Role for 4‐Hydroxynonenal, an Aldehydic Product of Lipid Peroxidation, in Disruption of Ion Homeostasis and Neuronal Death Induced by Amyloid β‐Peptide , 1997, Journal of neurochemistry.

[12]  R. Joynt.  Neurogenetics and Primary Care , 1997, Neurology.

[13]  H. Esterbauer,et al.  Monoclonal antibodies for detection of 4-hydroxynonenal modified proteins. , 1996, Free radical research.

[14]  E. Stadtman,et al.  A gain-of-function of an amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutant: An enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Hediger,et al.  Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate , 1996, Neuron.

[16]  M. Gurney,et al.  Benefit of vitamin E, riluzole, and gababapentin in a transgenic model of familial amyotrophic lateral sclerosis , 1996, Annals of neurology.

[17]  T. Deguchi,et al.  Immunohistochemical study on choline acetyltransferase in the spinal cord of patients with amyotrophic lateral sclerosis , 1995, Pathology international.

[18]  A. Levey,et al.  Selective loss of glial glutamate transporter GLT‐1 in amyotrophic lateral sclerosis , 1995, Annals of neurology.

[19]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[20]  V. Meininger,et al.  A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. , 1994, The New England journal of medicine.

[21]  J. Rothstein,et al.  Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. , 1992, The New England journal of medicine.

[22]  H. Esterbauer,et al.  Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. , 1991, Free radical biology & medicine.

[23]  J. Coyle,et al.  Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis , 1990, Annals of neurology.

[24]  P. Nunn,et al.  Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. , 1987, Science.