KEGG   PATHWAY: hsa05014Help
Entry
hsa05014                    Pathway                                

Name
Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human)
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.
Class
Human Diseases; Neurodegenerative diseases
BRITE hierarchy
Pathway map
hsa05014  Amyotrophic lateral sclerosis (ALS)
hsa05014

Ortholog table
Disease
H00058  Amyotrophic lateral sclerosis (ALS)
Drug
D00775  Riluzole (JAN/USAN/INN)
D10416  Belnacasan (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
7157  TP53; tumor protein p53 [KO:K04451]
5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
5532  PPP3CB; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
5533  PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
5534  PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268]
5535  PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268]
834  CASP1; caspase 1 [KO:K01370] [EC:3.4.22.36]
637  BID; BH3 interacting domain death agonist [KO:K04726]
596  BCL2; BCL2, apoptosis regulator [KO:K02161]
598  BCL2L1; BCL2 like 1 [KO:K04570]
581  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
572  BAD; BCL2 associated agonist of cell death [KO:K02158]
317  APAF1; apoptotic peptidase activating factor 1 [KO:K02084]
54205  CYCS; cytochrome c, somatic [KO:K08738]
842  CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
836  CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]
6647  SOD1; superoxide dismutase 1 [KO:K04565] [EC:1.15.1.1]
10452  TOMM40; translocase of outer mitochondrial membrane 40 [KO:K11518]
84134  TOMM40L; translocase of outer mitochondrial membrane 40 like [KO:K11518]
79139  DERL1; derlin 1 [KO:K11519]
100506742  CASP12; caspase 12 (gene/pseudogene) [KO:K04741] [EC:3.4.22.-]
4217  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
7124  TNF; tumor necrosis factor [KO:K03156]
7132  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
7133  TNFRSF1B; TNF receptor superfamily member 1B [KO:K05141]
1616  DAXX; death domain associated protein [KO:K02308]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
4842  NOS1; nitric oxide synthase 1 [KO:K13240] [EC:1.14.13.39]
9973  CCS; copper chaperone for superoxide dismutase [KO:K04569]
847  CAT; catalase [KO:K03781] [EC:1.11.1.6]
5630  PRPH; peripherin [KO:K07607]
4747  NEFL; neurofilament light [KO:K04572]
4741  NEFM; neurofilament medium [KO:K04573]
4744  NEFH; neurofilament heavy [KO:K04574]
57679  ALS2; ALS2, alsin Rho guanine nucleotide exchange factor [KO:K04575]
5868  RAB5A; RAB5A, member RAS oncogene family [KO:K07887]
5879  RAC1; Rac family small GTPase 1 [KO:K04392]
6506  SLC1A2; solute carrier family 1 member 2 [KO:K05613]
2890  GRIA1; glutamate ionotropic receptor AMPA type subunit 1 [KO:K05197]
2891  GRIA2; glutamate ionotropic receptor AMPA type subunit 2 [KO:K05198]
2902  GRIN1; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208]
2903  GRIN2A; glutamate ionotropic receptor NMDA type subunit 2A [KO:K05209]
2904  GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
2905  GRIN2C; glutamate ionotropic receptor NMDA type subunit 2C [KO:K05211]
2906  GRIN2D; glutamate ionotropic receptor NMDA type subunit 2D [KO:K05212]
2876  GPX1; glutathione peroxidase 1 [KO:K00432] [EC:1.11.1.9]
Compound
C00001  H2O
C00025  L-Glutamate
C00027  Hydrogen peroxide
C00062  L-Arginine
C00070  Copper
C00076  Calcium cation
C00533  Nitric oxide
C00704  O2.-
C16844  Hydroxyl radical
C16845  Peroxynitrite
Reference
  Authors
Pasinelli P, Brown RH
  Title
Molecular biology of amyotrophic lateral sclerosis: insights from genetics.
  Journal
Nat Rev Neurosci 7:710-23 (2006)
DOI:10.1038/nrn1971
Reference
  Authors
Goodall EF, Morrison KE
  Title
Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment.
  Journal
Expert Rev Mol Med 8:1-22 (2006)
DOI:10.1017/S1462399406010854
Reference
  Authors
Boillee S, Vande Velde C, Cleveland DW
  Title
ALS: a disease of motor neurons and their nonneuronal neighbors.
  Journal
Neuron 52:39-59 (2006)
DOI:10.1016/j.neuron.2006.09.018
Reference
  Authors
Julien JP.
  Title
Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.
  Journal
Cell 104:581-91 (2001)
DOI:10.1016/S0092-8674(01)00244-6
Reference
  Authors
Manfredi G, Xu Z
  Title
Mitochondrial dysfunction and its role in motor neuron degeneration in ALS.
  Journal
Mitochondrion 5:77-87 (2005)
DOI:10.1016/j.mito.2005.01.002
Reference
  Authors
Hand CK, Rouleau GA
  Title
Familial amyotrophic lateral sclerosis.
  Journal
Muscle Nerve 25:135-59 (2002)
DOI:10.1002/mus.10000
Reference
  Authors
Barber SC, Mead RJ, Shaw PJ
  Title
Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target.
  Journal
Biochim Biophys Acta 1762:1051-67 (2006)
DOI:10.1016/j.bbadis.2006.03.008
Reference
  Authors
von Lewinski F, Keller BU
  Title
Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS.
  Journal
Trends Neurosci 28:494-500 (2005)
DOI:10.1016/j.tins.2005.07.001
Reference
  Authors
Al-Chalabi A, Leigh PN
  Title
Recent advances in amyotrophic lateral sclerosis.
  Journal
Curr Opin Neurol 13:397-405 (2000)
Reference
  Authors
Guegan C, Przedborski S
  Title
Programmed cell death in amyotrophic lateral sclerosis.
  Journal
J Clin Invest 111:153-61 (2003)
DOI:10.1172/JCI17610
Reference
  Authors
Bendotti C, Bao Cutrona M, Cheroni C, Grignaschi G, Lo Coco D, Peviani M, Tortarolo M, Veglianese P, Zennaro E
  Title
Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase.
  Journal
Neurodegener Dis 2:128-34 (2005)
DOI:10.1159/000089617
Reference
  Authors
Emerit J, Edeas M, Bricaire F
  Title
Neurodegenerative diseases and oxidative stress.
  Journal
Biomed Pharmacother 58:39-46 (2004)
DOI:10.1016/j.biopha.2003.11.004
Reference
  Authors
Cleveland DW, Rothstein JD
  Title
From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS.
  Journal
Nat Rev Neurosci 2:806-19 (2001)
DOI:10.1038/35097565
Reference
  Authors
Bendotti C, Carri MT
  Title
Lessons from models of SOD1-linked familial ALS.
  Journal
Trends Mol Med 10:393-400 (2004)
DOI:10.1016/j.molmed.2004.06.009
Reference
  Authors
Robertson J, Kriz J, Nguyen MD, Julien JP
  Title
Pathways to motor neuron degeneration in transgenic mouse models.
  Journal
Biochimie 84:1151-60 (2002)
DOI:10.1016/S0300-9084(02)00025-1
Reference
  Authors
Bacman SR, Bradley WG, Moraes CT
  Title
Mitochondrial involvement in amyotrophic lateral sclerosis: trigger or target?
  Journal
Mol Neurobiol 33:113-31 (2006)
DOI:10.1385/MN:33:2:113
Reference
  Authors
Nishitoh H, Kadowaki H, Nagai A, Maruyama T, Yokota T, Fukutomi H, Noguchi T, Matsuzawa A, Takeda K, Ichijo H
  Title
ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
  Journal
Genes Dev 22:1451-64 (2008)
DOI:10.1101/gad.1640108
Reference
  Authors
Simpson EP, Yen AA, Appel SH
  Title
Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis.
  Journal
Curr Opin Rheumatol 15:730-6 (2003)
Reference
  Authors
Vila M, Przedborski S
  Title
Targeting programmed cell death in neurodegenerative diseases.
  Journal
Nat Rev Neurosci 4:365-75 (2003)
DOI:10.1038/nrn1100
Reference
  Authors
Volkel H, Scholz M, Link J, Selzle M, Werner P, Tunnemann R, Jung G, Ludolph AC, Reuter A
  Title
Superoxide dismutase mutations of familial amyotrophic lateral sclerosis and the oxidative inactivation of calcineurin.
  Journal
FEBS Lett 503:201-5 (2001)
DOI:10.1016/S0014-5793(01)02730-2
Reference
  Authors
Eve DJ, Dennis JS, Citron BA
  Title
Transcription factor p53 in degenerating spinal cords.
  Journal
Brain Res 1150:174-81 (2007)
DOI:10.1016/j.brainres.2007.02.088
Reference
  Authors
Van Damme P, Dewil M, Robberecht W, Van Den Bosch L
  Title
Excitotoxicity and amyotrophic lateral sclerosis.
  Journal
Neurodegener Dis 2:147-59 (2005)
DOI:10.1159/000089620
Reference
  Authors
Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE
  Title
Molecular and cellular function of ALS2/alsin: implication of membrane dynamics in neuronal development and degeneration.
  Journal
Neurochem Int 51:74-84 (2007)
DOI:10.1016/j.neuint.2007.04.010
Reference
  Authors
Kunita R, Otomo A, Mizumura H, Suzuki-Utsunomiya K, Hadano S, Ikeda JE
  Title
The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis.
  Journal
J Biol Chem 282:16599-611 (2007)
DOI:10.1074/jbc.M610682200
KO pathway
ko05014   

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