Amyotrophic lateral sclerosis (ALS) (WP2447)

Homo sapiens

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]


Anders Riutta , Alex Pico , Kristina Hanspers , Tyler Peryea , Susan Coort , Martina Summer-Kutmon , Egon Willighagen , Denise Slenter , Friederike Ehrhart , Finterly Hu , and Eric Weitz


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Homo sapiens


Rare Diseases


Cell Type Ontology

astrocyte neuron microglial cell

Disease Ontology

amyotrophic lateral sclerosis

Pathway Ontology

disease pathway


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
NO Metabolite hmdb:HMDB0003378
O2- Metabolite hmdb:HMDB0002168
Ca2+ Metabolite hmdb:HMDB0000464
NO Metabolite hmdb:HMDB0003378
L-Arginine Metabolite hmdb:HMDB0000517
ONOO- Metabolite hmdb:HMDB0002179
L-Glutamic acid Metabolite hmdb:HMDB0000148
L-Glutamic acid Metabolite hmdb:HMDB0000148
L-Glutamic acid Metabolite hmdb:HMDB0000148
Ca2+ Metabolite kegg.compound:C00076
NO Metabolite hmdb:HMDB0003378
NO Metabolite hmdb:HMDB0003378
Ca2+ Metabolite hmdb:HMDB0000464
Reactive oxygen species (ROS) Metabolite chebi:26523
PPP3CA GeneProduct ncbigene:5530
p38 GeneProduct ncbigene:1432
NOS1 GeneProduct ncbigene:4842
PPP3CB GeneProduct ncbigene:5532
RAB5A GeneProduct ncbigene:5868
MKK6 GeneProduct ncbigene:5608
NEFH GeneProduct ncbigene:4744
ALS2 GeneProduct ncbigene:57679
TNFalpha GeneProduct ncbigene:7124
NEFM GeneProduct ncbigene:4741
CAT GeneProduct ncbigene:847
MKK3 GeneProduct ncbigene:5605
RAC1 GeneProduct ncbigene:5879
PPP3CC GeneProduct ncbigene:5533
CCS GeneProduct ncbigene:9973
GPX1 GeneProduct ncbigene:2876
DAXX GeneProduct ncbigene:1616
ASK1 GeneProduct ncbigene:4217
NEFL GeneProduct ncbigene:4747
PRPH GeneProduct ncbigene:5630
TP53 GeneProduct ncbigene:7157
APAF1 GeneProduct ncbigene:317
CASP3 GeneProduct ncbigene:836
CASP9 GeneProduct ncbigene:842
CASP1 GeneProduct ncbigene:834
BID GeneProduct ncbigene:637
SOD1 GeneProduct ncbigene:6647
BCL2 GeneProduct ncbigene:596
BCL2L1 GeneProduct ncbigene:598
BAX GeneProduct ncbigene:581
BAD GeneProduct ncbigene:572
CASP12 GeneProduct ensembl:ENSG00000204403
TNFalpha GeneProduct ncbigene:7124
TNFR GeneProduct ncbigene:7132
SOD1 GeneProduct ncbigene:6647
ASK1 GeneProduct ncbigene:4217
SOD1 GeneProduct ncbigene:6647
SOD1 GeneProduct ncbigene:6647
CYTC Protein uniprot:P01034
EAAT2 Protein uniprot:P43004
Derlin-1 Protein ncbigene:79139
TOM40 Protein uniprot:O96008
GRIA1 Protein ncbigene:2890


  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