Entry
Name
Amyotrophic lateral sclerosis
Description
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive degeneration of motor neurons in the brain and spinal cord. In 90% of patients, ALS is sporadic, with no clear genetic linkage. On the other hand, the remaining 10% of cases show familial inheritance, with mutations in SOD1, TDP43(TARDBP), FUS, or C9orf72 genes being the most frequent causes. In spite of such difference, familial ALS and sporadic ALS have similarities in their pathological features. Proposed disease mechanisms contributing to motor neuron degeneration in ALS are: impaired proteostasis, aberrant RNA processing, mitochondrial disfunction and oxidative stress, microglia activation, and axonal dysfunction.
Class
Human Diseases; Neurodegenerative disease
BRITE hierarchy
Pathway map
ko05014 Amyotrophic lateral sclerosis
Ortholog table
Disease
H00058 Amyotrophic lateral sclerosis (ALS)
Orthology
K04726 BH3 interacting domain death agonist
K02161 apoptosis regulator Bcl-2
K04570 Bcl-2-like 1 (apoptosis regulator Bcl-X)
K02159 apoptosis regulator BAX
K02158 Bcl-2-antagonist of cell death
K02084 apoptotic protease-activating factor
K03942 NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:7.1.1.2 ]
K03943 NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:7.1.1.2 ]
K03944 NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955 NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1, acyl-carrier protein
K03956 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K11352 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K03957 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K11351 NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K03934 NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:7.1.1.2 ]
K03935 NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:7.1.1.2 ]
K03936 NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:7.1.1.2 ]
K03937 NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938 NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939 NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940 NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:7.1.1.2 ]
K03941 NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:7.1.1.2 ]
K03967 NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968 NADH dehydrogenase (ubiquinone) 1 subunit C2
K00234 succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:1.3.5.1 ]
K00235 succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:1.3.5.1 ]
K00236 succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237 succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411 ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:7.1.1.8 ]
K00412 ubiquinol-cytochrome c reductase cytochrome b subunit
K00413 ubiquinol-cytochrome c reductase cytochrome c1 subunit
K00414 ubiquinol-cytochrome c reductase core subunit 1
K00415 ubiquinol-cytochrome c reductase core subunit 2
K00416 ubiquinol-cytochrome c reductase subunit 6
K00417 ubiquinol-cytochrome c reductase subunit 7
K00418 ubiquinol-cytochrome c reductase subunit 8
K00419 ubiquinol-cytochrome c reductase subunit 9
K00420 ubiquinol-cytochrome c reductase subunit 10
K02262 cytochrome c oxidase subunit 3
K02261 cytochrome c oxidase subunit 2
K02263 cytochrome c oxidase subunit 4
K02264 cytochrome c oxidase subunit 5a
K02265 cytochrome c oxidase subunit 5b
K02266 cytochrome c oxidase subunit 6a
K02267 cytochrome c oxidase subunit 6b
K02268 cytochrome c oxidase subunit 6c
K02270 cytochrome c oxidase subunit 7a
K02271 cytochrome c oxidase subunit 7b
K02272 cytochrome c oxidase subunit 7c
K02273 cytochrome c oxidase subunit 8
K02132 F-type H+-transporting ATPase subunit alpha
K02136 F-type H+-transporting ATPase subunit gamma
K02134 F-type H+-transporting ATPase subunit delta
K02135 F-type H+-transporting ATPase subunit epsilon
K02126 F-type H+-transporting ATPase subunit a
K02127 F-type H+-transporting ATPase subunit b
K02128 F-type H+-transporting ATPase subunit c
K02138 F-type H+-transporting ATPase subunit d
K02137 F-type H+-transporting ATPase subunit O
K02131 F-type H+-transporting ATPase subunit 6
K02125 F-type H+-transporting ATPase subunit 8
K05862 voltage-dependent anion channel protein 1
K11518 mitochondrial import receptor subunit TOM40
K20858 calcium uniporter protein, mitochondrial
K10435 microtubule-associated protein 1 light chain
K12650 TRAF family member-associated NF-kappa-B activator
K23610 WD repeat-containing protein 41
K23611 guanine nucleotide exchange protein SMCR8
K23609 guanine nucleotide exchange protein C9orf72
K07901 Ras-related protein Rab-8A
K07925 Ras-related protein Rab-39B
K07874 Ras-related protein Rab-1A
K19730 autophagy-related protein 101
K08331 autophagy-related protein 13
K17589 RB1-inducible coiled-coil protein 1
K17985 activating molecule in BECN1-regulated autophagy protein 1
K17889 beclin 1-associated autophagy-related key regulator
K21246 nuclear receptor-binding factor 2
K17906 autophagy-related protein 2
K17908 autophagy-related protein 18
K04575 amyotrophic lateral sclerosis 2 protein
K07887 Ras-related protein Rab-5A
K04392 Ras-related C3 botulinum toxin substrate 1
K12192 charged multivesicular body protein 2B
K22913 phosphatidylinositol 3,5-bisphosphate 5-phosphatase [EC:3.1.3.-]
K04348 serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16 ]
K06268 serine/threonine-protein phosphatase 2B regulatory subunit
K13525 transitional endoplasmic reticulum ATPase
K03061 26S proteasome regulatory subunit T1
K03062 26S proteasome regulatory subunit T2
K03063 26S proteasome regulatory subunit T3
K03064 26S proteasome regulatory subunit T4
K03065 26S proteasome regulatory subunit T5
K03066 26S proteasome regulatory subunit T6
K03028 26S proteasome regulatory subunit N1
K03032 26S proteasome regulatory subunit N2
K03033 26S proteasome regulatory subunit N3
K06693 26S proteasome regulatory subunit N4
K03035 26S proteasome regulatory subunit N5
K03036 26S proteasome regulatory subunit N6
K03037 26S proteasome regulatory subunit N7
K03038 26S proteasome regulatory subunit N8
K03039 26S proteasome regulatory subunit N9
K03029 26S proteasome regulatory subunit N10
K03030 26S proteasome regulatory subunit N11
K03031 26S proteasome regulatory subunit N12
K06691 26S proteasome regulatory subunit N13
K10881 26 proteasome complex subunit DSS1
K23600 TAR DNA-binding protein 43
K13098 RNA-binding protein FUS
K12741 heterogeneous nuclear ribonucleoprotein A1/A3
K13158 heterogeneous nuclear ribonucleoprotein A2/B1
K16631 angiogenin [EC:3.1.27.-]
K12882 nuclear cap-binding protein subunit 1
K12892 serine/arginine-rich splicing factor 3
K12896 serine/arginine-rich splicing factor 7
K14284 nuclear RNA export factor
K14285 NTF2-related export protein 1/2
K14295 nuclear pore complex protein Nup50
K14296 nuclear pore complex protein Nup153
K14297 nuclear pore complex protein Nup98-Nup96
K14004 protein transport protein SEC13
K14300 nuclear pore complex protein Nup133
K14301 nuclear pore complex protein Nup107
K14302 nuclear pore complex protein Nup37
K14303 nuclear pore complex protein Nup160
K14304 nuclear pore complex protein Nup85
K14305 nuclear pore complex protein Nup43
K14306 nuclear pore complex protein Nup62
K14308 nuclear pore complex protein Nup54
K14309 nuclear pore complex protein Nup93
K14310 nuclear pore complex protein Nup205
K14311 nuclear pore complex protein Nup188
K14312 nuclear pore complex protein Nup155
K14313 nuclear pore complex protein Nup53
K14314 nuclear pore complex protein Nup210
K14316 nuclear pore complex protein Nup121
K14317 nuclear pore complex protein Nup214
K14318 nuclear pore complex protein Nup88
K12172 E3 SUMO-protein ligase RanBP2 [EC:2.3.2.-]
K22759 coiled-coil-helix-coiled-coil-helix domain-containing protein 10
K10707 vesicle-associated membrane protein-associated protein B
K09054 cyclic AMP-dependent transcription factor ATF-6 alpha
K04452 DNA damage-inducible transcript 3
K08852 serine/threonine-protein kinase/endoribonuclease IRE1 [EC:2.7.11.1 3.1.26.-]
K09027 X box-binding protein 1
K04741 caspase 12 [EC:3.4.22.-]
K08860 eukaryotic translation initiation factor 2-alpha kinase 3 [EC:2.7.11.1 ]
K03237 translation initiation factor 2 subunit 1
K04374 cyclic AMP-dependent transcription factor ATF-4
K04960 inositol 1,4,5-triphosphate receptor type 3
K20719 sigma non-opioid intracellular receptor
K03156 tumor necrosis factor superfamily, member 2
K03158 tumor necrosis factor receptor superfamily member 1A
K05141 tumor necrosis factor receptor superfamily member 1B
K02308 death-associated protein 6
K04569 copper chaperone for superoxide dismutase
K04572 neurofilament light polypeptide
K04573 neurofilament medium polypeptide (neurofilament 3)
K04574 neurofilament heavy polypeptide
K10396 kinesin family member 5
K16576 actin-related protein 10
K04647 huntingtin-associated protein 1
K10408 dynein axonemal heavy chain
K10410 dynein axonemal light intermediate chain 1
K10409 dynein axonemal intermediate chain 1
K11143 dynein axonemal intermediate chain 2
K10411 dynein axonemal light chain 1
K10412 dynein axonemal light chain 4
K05613 solute carrier family 1 (glial high affinity glutamate transporter), member 2
K05208 glutamate receptor ionotropic, NMDA 1
K05209 glutamate receptor ionotropic, NMDA 2A
K05210 glutamate receptor ionotropic, NMDA 2B
K05211 glutamate receptor ionotropic, NMDA 2C
K05212 glutamate receptor ionotropic, NMDA 2D
Compound
C04549 1-Phosphatidyl-1D-myo-inositol 3-phosphate
Reference
Authors
Brown RH, Al-Chalabi A
Title
Amyotrophic Lateral Sclerosis.
Journal
Reference
Authors
Webster CP, Smith EF, Shaw PJ, De Vos KJ
Title
Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?
Journal
Reference
Authors
Valko K, Ciesla L
Title
Amyotrophic lateral sclerosis.
Journal
Reference
Authors
Mathis S, Goizet C, Soulages A, Vallat JM, Masson GL
Title
Genetics of amyotrophic lateral sclerosis: A review.
Journal
Reference
Authors
Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC
Title
Controversies and priorities in amyotrophic lateral sclerosis.
Journal
Reference
Authors
Pasinelli P, Brown RH
Title
Molecular biology of amyotrophic lateral sclerosis: insights from genetics.
Journal
Reference
Authors
Goodall EF, Morrison KE
Title
Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment.
Journal
Reference
Authors
Smith EF, Shaw PJ, De Vos KJ
Title
The role of mitochondria in amyotrophic lateral sclerosis.
Journal
Reference
Authors
Kodavati M, Wang H, Hegde ML
Title
Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective.
Journal
Reference
Authors
Hervias I, Beal MF, Manfredi G
Title
Mitochondrial dysfunction and amyotrophic lateral sclerosis.
Journal
Reference
Authors
Bacman SR, Bradley WG, Moraes CT
Title
Mitochondrial involvement in amyotrophic lateral sclerosis: trigger or target?
Journal
Reference
Authors
Lin MT, Beal MF
Title
Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.
Journal
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
Reference
Authors
Simpson EP, Yen AA, Appel SH
Title
Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis.
Journal
Reference
Authors
Bendotti C, Carri MT
Title
Lessons from models of SOD1-linked familial ALS.
Journal
Reference
Authors
Robertson J, Kriz J, Nguyen MD, Julien JP
Title
Pathways to motor neuron degeneration in transgenic mouse models.
Journal
Reference
Authors
Eve DJ, Dennis JS, Citron BA
Title
Transcription factor p53 in degenerating spinal cords.
Journal
Reference
Authors
Bahar E, Kim H, Yoon H
Title
ER Stress-Mediated Signaling: Action Potential and Ca(2+) as Key Players.
Journal
Reference
Authors
Bezprozvanny I
Title
Calcium signaling and neurodegenerative diseases.
Journal
Reference
Authors
von Lewinski F, Keller BU
Title
Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS.
Journal
Reference
Authors
Julien JP.
Title
Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.
Journal
Reference
Authors
Hand CK, Rouleau GA
Title
Familial amyotrophic lateral sclerosis.
Journal
Reference
Authors
Barber SC, Mead RJ, Shaw PJ
Title
Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target.
Journal
Reference
Authors
Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK
Title
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.
Journal
Reference
Authors
Nguyen DKH, Thombre R, Wang J
Title
Autophagy as a common pathway in amyotrophic lateral sclerosis.
Journal
Reference
Authors
Lee JK, Shin JH, Lee JE, Choi EJ
Title
Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis.
Journal
Reference
Authors
Oakes JA, Davies MC, Collins MO
Title
TBK1: a new player in ALS linking autophagy and neuroinflammation.
Journal
Reference
Authors
Ramesh N, Pandey UB
Title
Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand.
Journal
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
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
Reference
Authors
Ruffoli R, Bartalucci A, Frati A, Fornai F
Title
Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis.
Journal
Reference
Authors
Menzies FM, Fleming A, Rubinsztein DC
Title
Compromised autophagy and neurodegenerative diseases.
Journal
Reference
Authors
Casterton RL, Hunt RJ, Fanto M
Title
Pathomechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus Through the Lens of Autophagy.
Journal
Reference
Authors
Lin G, Mao D, Bellen HJ
Title
Amyotrophic Lateral Sclerosis Pathogenesis Converges on Defects in Protein Homeostasis Associated with TDP-43 Mislocalization and Proteasome-Mediated Degradation Overload.
Journal
Reference
Authors
Hetz C, Mollereau B
Title
Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases.
Journal
Reference
Authors
Xiang C, Wang Y, Zhang H, Han F
Title
The role of endoplasmic reticulum stress in neurodegenerative disease.
Journal
Reference
Authors
Hughes D, Mallucci GR
Title
The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway.
Journal
Reference
Authors
Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ, Samali A
Title
Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders.
Journal
Reference
Authors
Turner BJ, Atkin JD
Title
ER stress and UPR in familial amyotrophic lateral sclerosis.
Journal
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
Reference
Authors
Walker AK, Atkin JD
Title
Stress signaling from the endoplasmic reticulum: A central player in the pathogenesis of amyotrophic lateral sclerosis.
Journal
Reference
Authors
Renaud L, Picher-Martel V, Codron P, Julien JP
Title
Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.
Journal
Reference
Authors
Nguyen HP, Van Broeckhoven C, van der Zee J
Title
ALS Genes in the Genomic Era and their Implications for FTD.
Journal
Reference
Authors
Atkin G, Paulson H
Title
Ubiquitin pathways in neurodegenerative disease.
Journal
Reference
Authors
Kim JM, Billington E, Reyes A, Notarianni T, Sage J, Agbas E, Taylor M, Monast I, Stanford JA, Agbas A
Title
Impaired Cu-Zn Superoxide Dismutase (SOD1) and Calcineurin (Cn) Interaction in ALS: A Presumed Consequence for TDP-43 and Zinc Aggregation in Tg SOD1(G93A) Rodent Spinal Cord Tissue.
Journal
Reference
Authors
Benarroch EE
Title
Sigma-1 receptor and amyotrophic lateral sclerosis.
Journal
Reference
Authors
Millecamps S, Julien JP
Title
Axonal transport deficits and neurodegenerative diseases.
Journal
Related pathway
ko03013 Nucleocytoplasmic transport
ko04141 Protein processing in endoplasmic reticulum
ko04810 Regulation of actin cytoskeleton
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