Amyotrophic lateral sclerosis (ALS) (Homo sapiens)

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Mitochondria1Endoplasmic reticulum (ER)AstrocyteLegendReducedexpressionMitochondriaAggregatesIncreased ROSAggregatesMitochondrial dysfunctionActivating mutationElevated glutamatelevelstBid Impairment of axonal transportDNA damageATP depletion Fall inmitochondrialmembrane potentialAbnormal Rab5 dependent endycytosis?Low Ca2+ buffering capacityIncreasedexpressionDNANeurofilament damageCup38O2-NOReactive OxygenSpecies (ROS)p53 Signaling PathwayCCSMAPK Signaling PathwayCYTCNEFLMKK3ALS2ASK1PPP3CANOS1DAXXRAB5APRPHApoptosisNOMKK6OHH2O2RAC1PPP3CBNEFHCATCa2+PPP3CCTNFalphaNEFMProteasomeGPX1H2Osynaptic transmission, glutamatergicPresynaptic 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


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

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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 Scholia

History

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CompareRevisionActionTimeUserComment
128125view13:18, 27 January 2024EweitzOntology Term : 'astrocyte' added !
128124view13:18, 27 January 2024EweitzOntology Term : 'neuron' added !
128123view13:17, 27 January 2024EweitzOntology Term : 'microglial cell' added !
128122view13:16, 27 January 2024EweitzRemove excessive padding
128121view13:15, 27 January 2024EweitzEconomize legend position
128120view13:14, 27 January 2024EweitzRefine layout, standardize case
113794view09:07, 24 November 2020Finterlysmall graphical update
113792view08:56, 24 November 2020Finterlymake pathways clickable
113789view17:09, 23 November 2020FinterlySmall graphical update and fixed links
109207view21:31, 26 February 2020KhanspersAdded mutation states
108062view13:19, 27 November 2019FehrhartOntology Term : 'amyotrophic lateral sclerosis' added !
106714view13:15, 17 September 2019MaintBotHMDB identifier normalization
105880view04:52, 16 August 2019KhanspersModified description
105527view06:00, 9 August 2019KhanspersModified description
96316view09:07, 8 March 2018Mkutmonremove old WP category
96258view16:25, 2 March 2018EgonwOntology Term : 'disease pathway' added !
96111view11:20, 18 February 2018EgonwReplaced mim-conversion with arrow for things that are not conversions.
96110view11:13, 18 February 2018EgonwMade a number of labels readable (again)
96105view14:38, 16 February 2018DeSlChanged MIMconversion to arrow between gene and metabolite
85186view14:39, 23 April 2016EgonwReplaced a mim-conversion with Arrow.
85057view10:52, 10 April 2016EgonwReplaced a Wikipedia ID with a ChEBI ID.
85049view10:22, 10 April 2016EgonwReplaced a Wikipedia ID with a ChEBI ID.
84415view21:47, 23 February 2016AlexanderPicoQuick edit to datanode annotation or property
79862view12:17, 21 April 2015Mkutmonfixed linkout to wikipedia for ROS
75221view21:48, 9 May 2014Khansperschnaged DNA from gene product to label
72245view20:53, 29 October 2013Khansperschanged pathway node xrefs from GO to WP
72040view13:49, 24 October 2013SusanConnected lines
71227view21:29, 15 October 2013MaintBotUpdated UniProt/TrEMBL data source
71226view21:21, 15 October 2013MaintBotUpdated KEGG xrefs
70574view18:04, 14 August 2013MaintBotFixed xref for p53
70573view17:59, 14 August 2013MaintBotFixed Wikipedia link for ROS
70572view15:05, 13 August 2013MetalmephistoAttempting to add ID for ROS
70571view15:00, 13 August 2013MetalmephistoChanged Metabolite ID
64563view17:47, 29 May 2013Khanspersadded lit ref
64292view04:22, 23 May 2013Khanspersadded pathway node
64291view04:09, 23 May 2013KhanspersModified description
64290view04:00, 23 May 2013Khanspersfinal draft
64289view03:56, 23 May 2013Khansperswork in progress
64288view03:52, 23 May 2013Khansperswork in progress
64271view20:45, 22 May 2013KhanspersPeriodical save, work in progress
64270view20:44, 22 May 2013KhanspersSpecify description
64269view20:35, 22 May 2013KhanspersPeriodical save, work in progress
64260view19:21, 22 May 2013KhanspersSpecify description
64259view19:17, 22 May 2013Khansperswork in progress
64256view19:09, 22 May 2013KhanspersPeriodical save, work in progress
64201view21:40, 21 May 2013Khansperswork in progress
64200view21:32, 21 May 2013Khansperswork in progress
64199view21:25, 21 May 2013KhanspersPeriodical save, work in progress
64198view21:15, 21 May 2013KhanspersPeriodical save, work in progress
64197view21:04, 21 May 2013KhanspersPeriodical save, work in progress

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+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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