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
Amyotrophic lateral sclerosis (ALS)
hsa05014

All organismsOrtholog table
Disease
H00058  
Amyotrophic lateral sclerosis (ALS)
Drug
D10416  
Belnacasan (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
7157  
K04451 tumor protein p53 | (RefSeq) TP53; tumor protein p53 [KO:K04451]
5530  
K04348 serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16] | (RefSeq) PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
5532  
K04348 serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16] | (RefSeq) PPP3CB; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
5533  
K04348 serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16] | (RefSeq) PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
5534  
K06268 serine/threonine-protein phosphatase 2B regulatory subunit | (RefSeq) PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268]
5535  
K06268 serine/threonine-protein phosphatase 2B regulatory subunit | (RefSeq) PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268]
834  
K01370 caspase 1 [EC:3.4.22.36] | (RefSeq) CASP1; caspase 1 [KO:K01370] [EC:3.4.22.36]
637  
K04726 BH3 interacting domain death agonist | (RefSeq) BID; BH3 interacting domain death agonist [KO:K04726]
596  
K02161 apoptosis regulator Bcl-2 | (RefSeq) BCL2; BCL2, apoptosis regulator [KO:K02161]
598  
K04570 Bcl-2-like 1 (apoptosis regulator Bcl-X) | (RefSeq) BCL2L1; BCL2 like 1 [KO:K04570]
581  
K02159 apoptosis regulator BAX | (RefSeq) BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
572  
K02158 Bcl-2-antagonist of cell death | (RefSeq) BAD; BCL2 associated agonist of cell death [KO:K02158]
317  
K02084 apoptotic protease-activating factor | (RefSeq) APAF1; apoptotic peptidase activating factor 1 [KO:K02084]
54205  
K08738 cytochrome c | (RefSeq) CYCS; cytochrome c, somatic [KO:K08738]
842  
K04399 caspase 9 [EC:3.4.22.62] | (RefSeq) CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
836  
K02187 caspase 3 [EC:3.4.22.56] | (RefSeq) CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]
6647  
K04565 superoxide dismutase; superoxide dismutase 1, soluble [KO:K04565] [EC:1.15.1.1]
10452  
K11518 mitochondrial import receptor subunit TOM40 | (RefSeq) TOMM40; translocase of outer mitochondrial membrane 40 [KO:K11518]
84134  
K11518 mitochondrial import receptor subunit TOM40 | (RefSeq) TOMM40L; translocase of outer mitochondrial membrane 40 like [KO:K11518]
79139  
K11519 Derlin-1 | (RefSeq) DERL1; derlin 1 [KO:K11519]
K04741 caspase 12 [EC:3.4.22.-] | (RefSeq) CASP12; caspase 12 (gene/pseudogene) [KO:K04741] [EC:3.4.22.-]
4217  
K04426 mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25] | (RefSeq) MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
7124  
K03156 tumor necrosis factor superfamily; tumor necrosis factor [KO:K03156]
7132  
K03158 tumor necrosis factor receptor superfamily member 1A | (RefSeq) TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
7133  
K05141 tumor necrosis factor receptor superfamily member 1B | (RefSeq) TNFRSF1B; TNF receptor superfamily member 1B [KO:K05141]
1616  
K02308 death-associated protein 6 | (RefSeq) DAXX; death domain associated protein [KO:K02308]
5606  
K04432 mitogen-activated protein kinase kinase 3 [EC:2.7.12.2] | (RefSeq) MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
5608  
K04433 mitogen-activated protein kinase kinase 6 [EC:2.7.12.2] | (RefSeq) MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5600  
K04441 p38 MAP kinase [EC:2.7.11.24] | (RefSeq) MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  
K04441 p38 MAP kinase [EC:2.7.11.24] | (RefSeq) MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  
K04441 p38 MAP kinase [EC:2.7.11.24] | (RefSeq) MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  
K04441 p38 MAP kinase [EC:2.7.11.24] | (RefSeq) MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
4842  
K13240 nitric-oxide synthase; nitric oxide synthase 1 [KO:K13240] [EC:1.14.13.39]
9973  
K04569 copper chaperone for superoxide dismutase | (RefSeq) CCS; copper chaperone for superoxide dismutase [KO:K04569]
847  
K03781 catalase [EC:1.11.1.6] | (RefSeq) CAT; catalase [KO:K03781] [EC:1.11.1.6]
5630  
K07607 peripherin | (RefSeq) PRPH; peripherin [KO:K07607]
4747  
K04572 neurofilament light polypeptide | (RefSeq) NEFL; neurofilament, light polypeptide [KO:K04572]
4741  
K04573 neurofilament medium polypeptide (neurofilament 3) | (RefSeq) NEFM; neurofilament, medium polypeptide [KO:K04573]
4744  
K04574 neurofilament heavy polypeptide | (RefSeq) NEFH; neurofilament heavy polypeptide [KO:K04574]
57679  
K04575 amyotrophic lateral sclerosis 2 protein | (RefSeq) ALS2; ALS2, alsin Rho guanine nucleotide exchange factor [KO:K04575]
5868  
K07887 Ras-related protein Rab-5A | (RefSeq) RAB5A; RAB5A, member RAS oncogene family [KO:K07887]
5879  
K04392 Ras-related C3 botulinum toxin substrate 1 | (RefSeq) RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
6506  
K05613 solute carrier family 1 (glial high affinity glutamate transporter); solute carrier family 1 member 2 [KO:K05613]
2890  
K05197 glutamate receptor 1 | (RefSeq) GRIA1; glutamate ionotropic receptor AMPA type subunit 1 [KO:K05197]
2891  
K05198 glutamate receptor 2 | (RefSeq) GRIA2; glutamate ionotropic receptor AMPA type subunit 2 [KO:K05198]
2902  
K05208 glutamate receptor ionotropic; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208]
2903  
K05209 glutamate receptor ionotropic; glutamate ionotropic receptor NMDA type subunit 2A [KO:K05209]
2904  
K05210 glutamate receptor ionotropic; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
2905  
K05211 glutamate receptor ionotropic; glutamate ionotropic receptor NMDA type subunit 2C [KO:K05211]
2906  
K05212 glutamate receptor ionotropic; glutamate ionotropic receptor NMDA type subunit 2D [KO:K05212]
2876  
K00432 glutathione peroxidase [EC:1.11.1.9] | (RefSeq) 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)
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)
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)
Reference
  Authors
Julien JP.
  Title
Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.
  Journal
Cell 104:581-91 (2001)
Reference
  Authors
Manfredi G, Xu Z
  Title
Mitochondrial dysfunction and its role in motor neuron degeneration in ALS.
  Journal
Mitochondrion 5:77-87 (2005)
Reference
  Authors
Hand CK, Rouleau GA
  Title
Familial amyotrophic lateral sclerosis.
  Journal
Muscle Nerve 25:135-59 (2002)
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)
Reference
  Authors
von Lewinski F, Keller BU
  Title
Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS.
  Journal
Trends Neurosci 28:494-500 (2005)
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)
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)
Reference
  Authors
Emerit J, Edeas M, Bricaire F
  Title
Neurodegenerative diseases and oxidative stress.
  Journal
Biomed Pharmacother 58:39-46 (2004)
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)
Reference
  Authors
Bendotti C, Carri MT
  Title
Lessons from models of SOD1-linked familial ALS.
  Journal
Trends Mol Med 10:393-400 (2004)
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)
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)
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)
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)
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)
Reference
  Authors
Eve DJ, Dennis JS, Citron BA
  Title
Transcription factor p53 in degenerating spinal cords.
  Journal
Brain Res 1150:174-81 (2007)
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)
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)
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)
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