Immunocytochemical study of the distribution of the free radical scavenging enzymes CU/ZN superoxide dismutase (SOD1); MN superoxide dismutase (MN SOD) and catalase in the normal human spinal cord and in motor neuron disease

Shaw, Pamela J.; Chinnery, Rachel M.; Thagesen, Helle; Borthwick, Gillian M.; Ince, Paul G.

doi:10.1016/s0022-510x(96)05316-6

Cited by 38 publications

(21 citation statements)

References 27 publications

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“…102 SOD1 enzyme activity in the motor cortex is normal in sporadic ALS patients, 103,104 and is reduced in SOD1 mutant familial ALS patients, 103,105 as compared with control subjects. SOD1 immunoreactivity in the lower motor neurons is more intense in sporadic cases, 106,107 and is less intense in SOD1 mutant familial cases. 108 SOD1 mRNA expression in the anterior horn cells is up-regulated 109 or normal 110 in sporadic cases, and is down-regulated in SOD1 mutant familial cases.…”

Section: Familial Als Associated With Sod1 Mutationmentioning

confidence: 88%

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

Shibata

Hirano

Yamamoto

et al. 2000

Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron system involvement, and is epidemiologically subclassified into sporadic, familial and endemic forms. About 20% of ALS families are associated with mutations in the gene for superoxide dismutase-1 (SOD1) encoded on chromosome 21q22.1. Several studies have pointed to a variety of functions of mutant SOD1, which has enhanced catalytic activity of the peroxynitrite-mediated tyrosine nitration, readily releases the reactive Cu ions, induces apoptotic cell death, has enhanced peroxidase activity, damages the mitochondria to release Ca2+, and forms SOD1-containing aggregates in the cytoplasm. Many of these studies have obtained evidence for increased oxidative damage in ALS. On the other hand, some reports disagree with oxidative damage involvement in SOD1 mutant ALS. In considering the findings of increased oxidative damage in mutant SOD1-expressing transgenic mice, it should be remembered that overexpression of mutant SOD1 may enhance oxidative stress generation from this enzyme. In this review, we present the clinicopathological features of SOD1 mutant familial ALS and its transgenic mouse model, and also discuss SOD1 mutation-related neurotoxicity, including SOD1 protein aggregation and post-translational protein modification.

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Section: Familial Als Associated With Sod1 Mutationmentioning

confidence: 88%

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

Shibata

Hirano

Yamamoto

et al. 2000

Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders

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“…Motor neurons normally have a very high content of SOD1 protein compared to other cells in the nervous system. Immunohistochemical localisation of SOD1 protein in motor neurons reveals the presence of SOD1 in the cell body and in the axonal processes extending to the neuromuscular junction [64,79] (Figs. 9 and 10).…”

Section: Cu/zn Superoxide Dismutase (Sod1) Mutations and Motor Neuronsmentioning

confidence: 99%

Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis

2000

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Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.

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“…Motor neurones differ from many other groups of cells in the CNS by their large size, their high ratio of axonal length to cell sorna diameter, their high metabolic rate, their high content of neurofilament proteins and free radical scavenging enzymes [70][71][72]. In relation to glutamate toxicity, two cell-specific molecular features of human motor neurones have been identified that may render this cell group unduly susceptible to calcium-mediated toxic events following glutamate receptor activation.…”

Section: Selective Vulnerability Of Motor Neuronesmentioning

confidence: 99%

“…2. The activity of the free-radical scavenging enzyme glutathione peroxidase [124], the protein expression of SOD1, Mn SOD and catalase [72] are all increased in ALS spinal cord, as is the expression of SOD1 mRNA in individual spinal motor neurones [ 125]. These changes may reflect a compensatory response to oxidative stress.…”

Section: Links Between Glutamate Receptor Activation and Free-radicalmentioning

confidence: 99%

Glutamate, excitotoxicity and amyotrophic lateral sclerosis

1997

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The "glutamate hypothesis" is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and CI-, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of "downstream" events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.

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Immunocytochemical study of the distribution of the free radical scavenging enzymes CU/ZN superoxide dismutase (SOD1); MN superoxide dismutase (MN SOD) and catalase in the normal human spinal cord and in motor neuron disease

Cited by 38 publications

References 27 publications

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis

Glutamate, excitotoxicity and amyotrophic lateral sclerosis

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