Amyotrophic lateral sclerosis (ALS) (Bos taurus)

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Mitochondria1AstrocyteEndoplasmic reticulum (ER)DNA damageIncreasedexpressionAggregatesAbnormal Rab5 dependent endycytosis?tBid MitochondriaAggregatesDNAMitochondrial dysfunctionImpairment of axonal transportReducedexpressionLow Ca2+ buffering capacityATP depletion Fall inmitochondrialmembrane potentialNeurofilament damageElevated glutamatelevelsIncreased ROSNOCST3ProteasomeMAP2K2DAXXRAB5AMAP2K6TNFO2-H2O2NOsynaptic transmission, glutamatergicALS2p53 Signaling PathwayH2OMAPK14NEFHCa2+RAC1NEFLCuApoptosisPPP3CBMAP3K5NOS1NEFMOHGPX1PRPHPPP3CCPPP3CACCSReactive OxygenSpecies (ROS)MAPK Signaling PathwayCATPresynaptic neuronMicroglial cellMotor neuronNOL-ArginineONOO-SLC1A2L-Glutamic acidL-Glutamic acidTP53Neuron deathAPAF1CASP3CASP9ActivationL-Glutamic acidIncrease incytosolic Ca2+Ca2+DERL1Accumulation ofmisfolded proteinsER stressDisturbance ofmitochondrial respirationCASP1BIDSOD1TOMM40BCL2BCL2L1BAXBADUbiquitin proteosomedysfunctionCASP12TNFTNFRSF1AGRIA1NONOSOD1ActivationCa2+MAP3K5ApoptosisReactive Oxygen Species (ROS)SOD1SOD1


Description

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.

Comments

HomologyMapper 
This pathway was inferred from Homo sapiens pathway WP2447_96316 with a 93.0% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

  1. Flomen R, Makoff A; ''Increased RNA editing in EAAT2 pre-mRNA from amyotrophic lateral sclerosis patients: involvement of a cryptic polyadenylation site.''; Neurosci Lett, 2011 PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
105922view11:45, 16 August 2019MaintBotHMDB identifier normalization
96317view09:08, 8 March 2018MkutmonUpdated homology conversion
89130view21:46, 22 August 2016AriuttaOntology Term : 'disease pathway' added !
85059view10:55, 10 April 2016EgonwReplaced a Wikipedia ID with a ChEBI ID.
85042view09:17, 10 April 2016EgonwReplaced a mim-conversion with mim-stimulation.
80870view15:29, 30 June 2015MkutmonNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ALS2GeneProductENSBTAG00000007395 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:57679
APAF1GeneProductENSBTAG00000021661 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:317
ApoptosisPathwayWP254 (WikiPathways)
BADGeneProductENSBTAG00000012511 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:572
BAXGeneProductENSBTAG00000013340 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:581
BCL2GeneProductENSBTAG00000019302 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:596
BCL2L1GeneProductENSBTAG00000006526 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:598
BIDGeneProductENSBTAG00000013988 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:637
CASP1GeneProductNo homologues found for original id L:834
CASP12GeneProductNo homologues found for original id En:ENSG00000204403
CASP3GeneProductENSBTAG00000015874 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:836
CASP9GeneProductENSBTAG00000002472 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:842
CATGeneProductENSBTAG00000020980 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:847
CCSGeneProductENSBTAG00000004343 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:9973
CST3ProteinENSBTAG00000000598 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = S:P01034
Ca2+MetaboliteC00076 (KEGG Compound)
Ca2+MetaboliteHMDB00464 (HMDB)
CuMetaboliteHMDB00657 (HMDB)
DAXXGeneProductENSBTAG00000016830 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:1616
DERL1ProteinENSBTAG00000020693 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:79139
GPX1GeneProductNo homologues found for original id L:2876
GRIA1ProteinENSBTAG00000005800 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:2890
H2O2MetaboliteHMDB03125 (HMDB)
H2OMetaboliteHMDB02111 (HMDB)
L-ArginineMetaboliteHMDB00517 (HMDB)
L-Glutamic acidMetaboliteHMDB00148 (HMDB)
MAP2K2GeneProductENSBTAG00000024450 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5605
MAP2K6GeneProductENSBTAG00000001609 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5608
MAP3K5GeneProductENSBTAG00000009065 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4217
MAPK Signaling PathwayPathwayWP382 (WikiPathways)
MAPK14GeneProductENSBTAG00000020783 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:1432
NEFHGeneProductENSBTAG00000013147 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4744
NEFLGeneProductENSBTAG00000021949 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4747
NEFMGeneProductENSBTAG00000039530 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4741
NOMetaboliteHMDB03378 (HMDB)
NOS1GeneProductENSBTAG00000002023 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4842
O2-MetaboliteHMDB02168 (HMDB)
OHMetaboliteHMDB01039 (HMDB)
ONOO-MetaboliteHMDB02179 (HMDB)
PPP3CAGeneProductENSBTAG00000016005 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5530
PPP3CBGeneProductENSBTAG00000046024 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5532
PPP3CCGeneProductENSBTAG00000020133 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5533
PRPHGeneProductENSBTAG00000017864 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5630
ProteasomePathwayWP183 (WikiPathways)
RAB5AGeneProductENSBTAG00000046385 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5868
RAC1GeneProductENSBTAG00000009233 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5879
Reactive Oxygen Species (ROS)MetaboliteCHEBI:26523 (ChEBI)
Reactive Oxygen Species (ROS)MetaboliteCHEBI:26523 (ChEBI)
SLC1A2ProteinENSBTAG00000012628 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = S:P43004
SOD1GeneProductENSBTAG00000027412 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:6647
TNFGeneProductENSBTAG00000025471 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:7124
TNFRSF1AGeneProductENSBTAG00000004211 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:7132
TOMM40ProteinENSBTAG00000001781 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = S:O96008
TP53GeneProductENSBTAG00000001069 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:7157
p53 Signaling PathwayPathwayWP707 (WikiPathways)
synaptic transmission, glutamatergicPathwayWP2267 (WikiPathways)

Annotated Interactions

No annotated interactions
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