Amyotrophic lateral sclerosis (ALS) (Homo sapiens)

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Mitochondria1AstrocyteLegendEndoplasmic reticulum (ER)AggregatestBid ATP depletion Fall inmitochondrialmembrane potentialLow Ca2+ buffering capacityIncreased ROSReducedexpressionIncreasedexpressionDNA damageActivating mutationAggregatesDNAMitochondrial dysfunctionNeurofilament damageElevated glutamatelevelsMitochondriaAbnormal Rab5 dependent endycytosis?Impairment of axonal transportPPP3CAGPX1synaptic transmission, glutamatergicH2Op38NOPPP3CCApoptosisO2-CATMKK6DAXXp53 Signaling PathwayMAPK Signaling PathwayH2O2CYTCPRPHNEFLCuRAC1ProteasomeMKK3Reactive OxygenSpecies (ROS)Ca2+NOS1NONEFMASK1OHNEFHALS2RAB5ACCSTNFalphaPPP3CBPresynaptic neuronMicroglial cellMotor neuronNOL-ArginineONOO-EAAT2L-Glutamic acidL-Glutamic acidTP53Neuron deathAPAF1CASP3CASP9ActivationL-Glutamic acidIncrease incytosolic Ca2+Ca2+Derlin-1Accumulation ofmisfolded proteinsER stressDisturbance ofmitochondrial respirationCASP1BIDSOD1TOM40BCL2BCL2L1BAXBADUbiquitin proteosomedysfunctionCASP12TNFalphaTNFRGRIA1NONOSOD1ActivationCa2+ASK1ApoptosisReactive Oxygen Species (ROS)SOD1SOD1


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. Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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Ontology Terms



  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 Scholia


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109207view21:31, 26 February 2020KhanspersAdded mutation states
108062view13:19, 27 November 2019FehrhartOntology Term : 'amyotrophic lateral sclerosis' added !
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105880view04:52, 16 August 2019KhanspersModified description
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External references


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NameTypeDatabase referenceComment
ALS2GeneProduct57679 (Entrez Gene)
APAF1GeneProduct317 (Entrez Gene)
ASK1GeneProduct4217 (Entrez Gene)
ApoptosisPathwayWP254 (WikiPathways)
BADGeneProduct572 (Entrez Gene)
BAXGeneProduct581 (Entrez Gene)
BCL2GeneProduct596 (Entrez Gene)
BCL2L1GeneProduct598 (Entrez Gene)
BIDGeneProduct637 (Entrez Gene)
CASP12GeneProductENSG00000204403 (Ensembl)
CASP1GeneProduct834 (Entrez Gene)
CASP3GeneProduct836 (Entrez Gene)
CASP9GeneProduct842 (Entrez Gene)
CATGeneProduct847 (Entrez Gene)
CCSGeneProduct9973 (Entrez Gene)
CYTCProteinP01034 (Uniprot-TrEMBL)
Ca2+MetaboliteC00076 (KEGG Compound)
Ca2+MetaboliteHMDB0000464 (HMDB)
CuMetaboliteHMDB0000657 (HMDB)
DAXXGeneProduct1616 (Entrez Gene)
Derlin-1Protein79139 (Entrez Gene)
EAAT2ProteinP43004 (Uniprot-TrEMBL)
GPX1GeneProduct2876 (Entrez Gene)
GRIA1Protein2890 (Entrez Gene)
H2O2MetaboliteHMDB0003125 (HMDB)
H2OMetaboliteHMDB0002111 (HMDB)
L-ArginineMetaboliteHMDB0000517 (HMDB)
L-Glutamic acidMetaboliteHMDB0000148 (HMDB)
MAPK Signaling PathwayPathwayWP382 (WikiPathways)
MKK3GeneProduct5605 (Entrez Gene)
MKK6GeneProduct5608 (Entrez Gene)
NEFHGeneProduct4744 (Entrez Gene)
NEFLGeneProduct4747 (Entrez Gene)
NEFMGeneProduct4741 (Entrez Gene)
NOMetaboliteHMDB0003378 (HMDB)
NOS1GeneProduct4842 (Entrez Gene)
O2-MetaboliteHMDB0002168 (HMDB)
OHMetaboliteHMDB0001039 (HMDB)
ONOO-MetaboliteHMDB0002179 (HMDB)
PPP3CAGeneProduct5530 (Entrez Gene)
PPP3CBGeneProduct5532 (Entrez Gene)
PPP3CCGeneProduct5533 (Entrez Gene)
PRPHGeneProduct5630 (Entrez Gene)
ProteasomePathwayWP183 (WikiPathways)
RAB5AGeneProduct5868 (Entrez Gene)
RAC1GeneProduct5879 (Entrez Gene)
Reactive Oxygen Species (ROS)MetaboliteCHEBI:26523 (ChEBI)
Reactive Oxygen Species (ROS)MetaboliteCHEBI:26523 (ChEBI)
SOD1GeneProduct6647 (Entrez Gene)
TNFRGeneProduct7132 (Entrez Gene)
TNFalphaGeneProduct7124 (Entrez Gene)
TOM40ProteinO96008 (Uniprot-TrEMBL)
TP53GeneProduct7157 (Entrez Gene)
p38GeneProduct1432 (Entrez Gene)
p53 Signaling PathwayPathwayWP707 (WikiPathways)
synaptic transmission, glutamatergicPathwayWP2267 (WikiPathways)

Annotated Interactions

No annotated interactions

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