Amyotrophic lateral sclerosis (ALS) (Homo sapiens)

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Mitochondria Endoplasmic reticulum (ER) Astrocyte Mitochondrial dysfunction DNA damage Mitochondria Increased expression Elevated glutamate levels Aggregates Abnormal Rab5 dependent endycytosis? Reduced expression DNA Increased ROS Impairment of axonal transport Aggregates Neurofilament damage tBid ATP depletion Fall in mitochondrial membrane potential Low Ca2+ buffering capacity Ca2+ H2O2 p38 Cu p53 Signaling Pathway Apoptosis NOS1 CYTC RAB5A synaptic transmission, glutamatergic Proteasome NO NEFH ALS2 TNFalpha NEFM H2O CAT Reactive Oxygen Species (ROS) RAC1 OH NO CCS MAPK Signaling Pathway GPX1 DAXX O2- ASK1 NEFL Ca2+ PRPH MKK6 MKK3 PPP3CA PPP3CB PPP3CC Presynaptic neuron Microglial cell Motor neuron NO L-Arginine ONOO- EAAT2 L-Glutamic acid L-Glutamic acid TP53 Neuron death APAF1 CASP3 CASP9 Activation L-Glutamic acid Increase in cytosolic Ca2+ Ca2+ Derlin-1 Accumulation of misfolded proteins ER stress Disturbance of mitochondrial respiration CASP1 BID SOD1 TOM40 BCL2 BCL2L1 BAX BAD Ubiquitin proteosome dysfunction CASP12 TNFalpha TNFR GRIA1 NO NO SOD1 Activation ASK1 Apoptosis Reactive Oxygen Species (ROS) SOD1 SOD1 Name: Amyotrophic lateral sclerosis (ALS) Organism: Homo sapiens


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.

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Ontology Terms

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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

History

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RevisionActionTimeUserComment
96316view 02:07, 8 March 2018Mkutmonremove old WP category
96258view 09:25, 2 March 2018EgonwOntology Term : 'disease pathway' added !
96111view 04:20, 18 February 2018EgonwReplaced mim-conversion with arrow for things that are not conversions.
96110view 04:13, 18 February 2018EgonwMade a number of labels readable (again)
96105view 07:38, 16 February 2018DeSlChanged MIMconversion to arrow between gene and metabolite
85186view 07:39, 23 April 2016EgonwReplaced a mim-conversion with Arrow.
85057view 03:52, 10 April 2016EgonwReplaced a Wikipedia ID with a ChEBI ID.
85049view 03:22, 10 April 2016EgonwReplaced a Wikipedia ID with a ChEBI ID.
84415view 14:47, 23 February 2016AlexanderPicoQuick edit to datanode annotation or property
79862view 05:17, 21 April 2015Mkutmonfixed linkout to wikipedia for ROS
75221view 14:48, 9 May 2014Khansperschnaged DNA from gene product to label
72245view 13:53, 29 October 2013Khansperschanged pathway node xrefs from GO to WP
72040view 06:49, 24 October 2013SusanConnected lines
71227view 14:29, 15 October 2013MaintBotUpdated UniProt/TrEMBL data source
71226view 14:21, 15 October 2013MaintBotUpdated KEGG xrefs
70574view 11:04, 14 August 2013MaintBotFixed xref for p53
70573view 10:59, 14 August 2013MaintBotFixed Wikipedia link for ROS
70572view 08:05, 13 August 2013MetalmephistoAttempting to add ID for ROS
70571view 08:00, 13 August 2013MetalmephistoChanged Metabolite ID
64563view 10:47, 29 May 2013Khanspersadded lit ref
64292view 21:22, 22 May 2013Khanspersadded pathway node
64291view 21:09, 22 May 2013KhanspersModified description
64290view 21:00, 22 May 2013Khanspersfinal draft
64289view 20:56, 22 May 2013Khansperswork in progress
64288view 20:52, 22 May 2013Khansperswork in progress
64271view 13:45, 22 May 2013KhanspersPeriodical save, work in progress
64270view 13:44, 22 May 2013KhanspersSpecify description
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External references

DataNodes

View all...
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+MetaboliteHMDB00464 (HMDB)
CuMetaboliteHMDB00657 (HMDB)
DAXXGeneProduct1616 (Entrez Gene)
Derlin-1Protein79139 (Entrez Gene)
EAAT2ProteinP43004 (Uniprot-TrEMBL)
GPX1GeneProduct2876 (Entrez Gene)
GRIA1Protein2890 (Entrez Gene)
H2O2MetaboliteHMDB03125 (HMDB)
H2OMetaboliteHMDB02111 (HMDB)
L-ArginineMetaboliteHMDB00517 (HMDB)
L-Glutamic acidMetaboliteHMDB00148 (HMDB)
MAPK Signaling PathwayPathwayWP382 (WikiPathways)
MKK3GeneProduct5605 (Entrez Gene)
MKK6GeneProduct5608 (Entrez Gene)
NEFHGeneProduct4744 (Entrez Gene)
NEFLGeneProduct4747 (Entrez Gene)
NEFMGeneProduct4741 (Entrez Gene)
NOMetaboliteHMDB03378 (HMDB)
NOS1GeneProduct4842 (Entrez Gene)
O2-MetaboliteHMDB02168 (HMDB)
OHMetaboliteHMDB01039 (HMDB)
ONOO-MetaboliteHMDB02179 (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

<cite>No annotated interactions</cite>