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Entry
map05014                    Pathway                                

Name
Amyotrophic lateral sclerosis (ALS)
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
map05014  Amyotrophic lateral sclerosis (ALS)
map05014

Ortholog table
Disease
H00058  Amyotrophic lateral sclerosis (ALS)
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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