Document Information

PMID 16026864  (  )
Title Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS.
Abstract Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca(2+)-dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca(2+)-buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca(2+) buffers are valuable because they facilitate rapid relaxation times of Ca(2+) transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca(2+) buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca(2+) disregulation and excitotoxic cell damage. 37073 Gottingen, Germany.

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))16superoxide dismutase 1 | SOD1 | SOD-transgenic | SOD1-related |
12680VEGFAvascular endothelial growth factor A3VEGF |
9704PVALBparvalbumin3parvalbumin |
4572GRIA2glutamate receptor, ionotropic, AMPA 22GluR2 |
19986CYCScytochrome c, somatic1cytochrome c |
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 21EAAT2 |
3665FGF1fibroblast growth factor 1 (acidic)1endothelial cell growth factor |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2induced by mutations in the enzyme superoxide dismutase 1 (SOD1) SOD1
4572GRIA2glutamate receptor, ionotropic, AMPA 2GluR21.3of highly Ca 2 -permeable AMPA receptors which lack the GluR2 unit 4 14 15 and 16 a high neurofilament content
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2EAAT21.0can be caused by oxidative damage to the glutamate transporter EAAT2 or by aberrant RNA processing 22
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2For the well-studied familial form of ALS induced by mutant SOD1 the involvement of Ca 2 has been demonstrated in cell
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2given by the inhibition of glial glutamate transport by mutant SOD1 and the consecutive disturbance of Ca 2 homeostasis by excitotoxic
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1-related2.2the importance of Ca 2 -permeable AMPA receptors in mutant SOD1-related ALS
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2Ca 2 -permeable AMPA receptors and survival times of transgenic SOD1 mice were significantly increased following chronic treatment with AMPA receptor
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2addition to glutamate receptors in mediating the toxicity of mutant SOD1 in motoneurons
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2-permeable AMPA receptors was further underlined by cross-breeding of transgenic SOD1 mice with mice that showed markedly reduced Ca 2 permeability
4572GRIA2glutamate receptor, ionotropic, AMPA 2GluR21.3Ca 2 permeability of AMPA/kainate AMPA kainate receptors due to GluR2 overexpression
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2Aggregates containing mutant SOD1 have been found within the mitochondrial matrix 42 43 and
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2Most interestingly recent work provided evidence that mutant SOD1 might disrupt association of complex IV (cytochrome cytochrome c with
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2This has been demonstrated for cultured motoneurons expressing mutant SOD1 49 and is in line with a study of motoneurons
12680VEGFAvascular endothelial growth factor AVEGF2.2that eliminates the ability of vascular endothelial-cell growth factor (VEGF) VEGF to respond to tissue hypoxia 54
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2Cross-breeding these mice with the SOD1 mutants severely enhanced motoneuron degeneration 55 whereas treatment of SOD-transgenic
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD-transgenic2.2SOD1 mutants severely enhanced motoneuron degeneration 55 whereas treatment of SOD-transgenic mice with VEGF delayed progression of symptoms and prolonged survival
12680VEGFAvascular endothelial growth factor AVEGF2.2enhanced motoneuron degeneration 55 whereas treatment of SOD-transgenic mice with VEGF delayed progression of symptoms and prolonged survival 56 and 57
12680VEGFAvascular endothelial growth factor AVEGF2.2Although direct neurotrophic effects of VEGF might contribute to these phenomena motoneurons seem selectively vulnerable to
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2Briefly mitochondrial respiration can be disturbed by mutations in SOD1 hypoxia Ca 2 overload or alterations in the mitochondrial genome
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD12.2disturbance of mitochondrial respiration by mutant superoxide dismutase 1 (SOD1) SOD1 or hypoxia results in increased formation of reactive oxygen species
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase 11.0als is sporadic in 90% of cases; the remaining 10% are of genetic origin with a subset being induced by mutations in the enzyme superoxide dismutase 1 sod1 .
9704PVALBparvalbuminparvalbumin1.0early evidence for involvement of ca 2+ was provided by the observation that ca 2+ binding proteins such as calbindin d28k and parvalbumin were absent in motoneuron populations lost early in als cortical spinal and lower cranial nerve motoneurons whereas motoneurons damaged late or infrequently in the disease those of onuf's nucleus and
9704PVALBparvalbuminparvalbumin1.0rons whereas motoneurons damaged late or infrequently in the disease those of onuf's nucleus and the oculomotor trochlear and abducens nerves expressed markedly higher levels of calbindin d28k and/or parvalbumin [13] .
19986CYCScytochrome c, somaticcytochrome c1.0most interestingly recent work provided evidence that mutant sod1 might disrupt association of complex iv cytochrome c with the inner mitochondrial membrane and by this interfere with mitochondrial respiration [48] .
3665FGF1fibroblast growth factor 1 (acidic)endothelial cell growth factor1.0in line with these observations als like symptoms and neuropathology can be produced in mice by a targeted deletion that eliminates the ability of vascular endothelial cell growth factor vegf to respond to tissue hypoxia [54] .
9704PVALBparvalbuminparvalbumin1.0it is interesting to note that experimentally measured buffering capacities correlated well with the expression profiles of ca 2+ binding proteins such as parvalbumin and calbindin d28k supporting the notion that they might represent the major structural components responsible for endogenous ca 2+ buffering.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase 11.0als related disturbance of mitochondrial respiration by mutant superoxide dismutase 1 sod1 or hypoxia results in increased formation of reactive oxygen species ros 48 and 49 .