Amyotrophic lateral sclerosis (ALS) (WP3243)

Bos taurus

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial ALS (FALS) cases, is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS). Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess increases intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions , which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, affecting axonal transport. Collectively, these mechanisms are predicted to disturb cellular homeostasis, ultimately triggering motor neuron death.

Authors

Martina Summer-Kutmon , Egon Willighagen , and Anders Riutta

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

disease pathway

Participants

Label Type Compact URI Comment
H2O2 Metabolite hmdb:HMDB0003125
Cu Metabolite hmdb:HMDB0000657
NO Metabolite hmdb:HMDB0003378
H2O Metabolite hmdb:HMDB0002111
Reactive OxygenSpecies (ROS) Metabolite chebi:26523
OH Metabolite hmdb:HMDB0001039
O2- Metabolite hmdb:HMDB0002168
Ca2+ Metabolite hmdb:HMDB0000464
L-Arginine Metabolite hmdb:HMDB0000517
ONOO- Metabolite hmdb:HMDB0002179
L-Glutamic acid Metabolite hmdb:HMDB0000148
Ca2+ Metabolite kegg.compound:C00076
Reactive Oxygen Species (ROS) Metabolite chebi:26523
PPP3CA GeneProduct ensembl:ENSBTAG00000016005 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5530
MAPK14 GeneProduct ensembl:ENSBTAG00000020783 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:1432
NOS1 GeneProduct ensembl:ENSBTAG00000002023 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4842
PPP3CB GeneProduct ensembl:ENSBTAG00000046024 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5532
RAB5A GeneProduct ensembl:ENSBTAG00000046385 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5868
MAP2K6 GeneProduct ensembl:ENSBTAG00000001609 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5608
NEFH GeneProduct ensembl:ENSBTAG00000013147 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4744
ALS2 GeneProduct ensembl:ENSBTAG00000007395 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:57679
TNF GeneProduct ensembl:ENSBTAG00000025471 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:7124
NEFM GeneProduct ensembl:ENSBTAG00000039530 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4741
CAT GeneProduct ensembl:ENSBTAG00000020980 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:847
MAP2K2 GeneProduct ensembl:ENSBTAG00000024450 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5605
RAC1 GeneProduct ensembl:ENSBTAG00000009233 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5879
PPP3CC GeneProduct ensembl:ENSBTAG00000020133 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5533
CCS GeneProduct ensembl:ENSBTAG00000004343 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:9973
DAXX GeneProduct ensembl:ENSBTAG00000016830 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:1616
MAP3K5 GeneProduct ensembl:ENSBTAG00000009065 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4217
NEFL GeneProduct ensembl:ENSBTAG00000021949 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4747
PRPH GeneProduct ensembl:ENSBTAG00000017864 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5630
TP53 GeneProduct ensembl:ENSBTAG00000001069 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:7157
APAF1 GeneProduct ensembl:ENSBTAG00000021661 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:317
CASP3 GeneProduct ensembl:ENSBTAG00000015874 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:836
CASP9 GeneProduct ensembl:ENSBTAG00000002472 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:842
BID GeneProduct ensembl:ENSBTAG00000013988 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:637
SOD1 GeneProduct ensembl:ENSBTAG00000027412 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:6647
BCL2 GeneProduct ensembl:ENSBTAG00000019302 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:596
BCL2L1 GeneProduct ensembl:ENSBTAG00000006526 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:598
BAX GeneProduct ensembl:ENSBTAG00000013340 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:581
BAD GeneProduct ensembl:ENSBTAG00000012511 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:572
TNFRSF1A GeneProduct ensembl:ENSBTAG00000004211 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:7132
CST3 Protein ensembl:ENSBTAG00000000598 Homology Mapping from Homo sapiens to Bos taurus: Original ID = S:P01034
SLC1A2 Protein ensembl:ENSBTAG00000012628 Homology Mapping from Homo sapiens to Bos taurus: Original ID = S:P43004
DERL1 Protein ensembl:ENSBTAG00000020693 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:79139
TOMM40 Protein ensembl:ENSBTAG00000001781 Homology Mapping from Homo sapiens to Bos taurus: Original ID = S:O96008
GRIA1 Protein ensembl:ENSBTAG00000005800 Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:2890

References

  1. Increased RNA editing in EAAT2 pre-mRNA from amyotrophic lateral sclerosis patients: involvement of a cryptic polyadenylation site. Flomen R, Makoff A. Neurosci Lett. 2011 Jun 22;497(2):139–43. PubMed Europe PMC Scholia