KEGG PATHWAY: map05014

PATHWAY: map05014

Entry

map05014                    Pathway

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

Pathway map

map05014

Amyotrophic lateral sclerosis

Disease

H00058

Amyotrophic lateral sclerosis (ALS)

Reference

PMID:28700839

Authors

Brown RH, Al-Chalabi A

Title

Amyotrophic Lateral Sclerosis.

Journal

N Engl J Med 377:162-172 (2017)
DOI:10.1056/NEJMra1603471

Reference

PMID:28512398

Authors

Webster CP, Smith EF, Shaw PJ, De Vos KJ

Title

Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

Journal

Front Mol Neurosci 10:123 (2017)
DOI:10.3389/fnmol.2017.00123

Reference

PMID:30879475

Authors

Valko K, Ciesla L

Title

Amyotrophic lateral sclerosis.

Journal

Prog Med Chem 58:63-117 (2019)
DOI:10.1016/bs.pmch.2018.12.001

Reference

PMID:30870681

Authors

Mathis S, Goizet C, Soulages A, Vallat JM, Masson GL

Title

Genetics of amyotrophic lateral sclerosis: A review.

Journal

J Neurol Sci 399:217-226 (2019)
DOI:10.1016/j.jns.2019.02.030

Reference

PMID:23415570

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

Lancet Neurol 12:310-22 (2013)
DOI:10.1016/S1474-4422(13)70036-X

Reference

PMID:16924260

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

PMID:16723044

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

PMID:28669745

Authors

Smith EF, Shaw PJ, De Vos KJ

Title

The role of mitochondria in amyotrophic lateral sclerosis.

Journal

Neurosci Lett 710:132933 (2019)
DOI:10.1016/j.neulet.2017.06.052

Reference

PMID:32344665

Authors

Kodavati M, Wang H, Hegde ML

Title

Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective.

Journal

Cells 9:E1065 (2020)
DOI:10.3390/cells9041065

Reference

PMID:16372325

Authors

Hervias I, Beal MF, Manfredi G

Title

Mitochondrial dysfunction and amyotrophic lateral sclerosis.

Journal

Muscle Nerve 33:598-608 (2006)
DOI:10.1002/mus.20489

Reference

PMID:16603792

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

PMID:17051205

Authors

Lin MT, Beal MF

Title

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.

Journal

Nature 443:787-95 (2006)
DOI:10.1038/nature05292

Reference

PMID:16909017

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

PMID:14569202

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)
DOI:10.1097/00002281-200311000-00008

Reference

PMID:15310460

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

PMID:12595144

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

PMID:17434459

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

PMID:27649160

Authors

Bahar E, Kim H, Yoon H

Title

ER Stress-Mediated Signaling: Action Potential and Ca(2+) as Key Players.

Journal

Int J Mol Sci 17:E1558 (2016)
DOI:10.3390/ijms17091558

Reference

PMID:19230774

Authors

Bezprozvanny I

Title

Calcium signaling and neurodegenerative diseases.

Journal

Trends Mol Med 15:89-100 (2009)
DOI:10.1016/j.molmed.2009.01.001

Reference

PMID:16026864

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

PMID:11239414

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

PMID:11870681

Authors

Hand CK, Rouleau GA

Title

Familial amyotrophic lateral sclerosis.

Journal

Muscle Nerve 25:135-59 (2002)
DOI:10.1002/mus.10000

Reference

PMID:16713195

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

PMID:30837838

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

Front Mol Neurosci 12:25 (2019)
DOI:10.3389/fnmol.2019.00025

Reference

PMID:29626651

Authors

Nguyen DKH, Thombre R, Wang J

Title

Autophagy as a common pathway in amyotrophic lateral sclerosis.

Journal

Neurosci Lett 697:34-48 (2019)
DOI:10.1016/j.neulet.2018.04.006

Reference

PMID:26264610

Authors

Lee JK, Shin JH, Lee JE, Choi EJ

Title

Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis.

Journal

Biochim Biophys Acta 1852:2517-24 (2015)
DOI:10.1016/j.bbadis.2015.08.005

Reference

PMID:28148298

Authors

Oakes JA, Davies MC, Collins MO

Title

TBK1: a new player in ALS linking autophagy and neuroinflammation.

Journal

Mol Brain 10:5 (2017)
DOI:10.1186/s13041-017-0287-x

Reference

PMID:28878620

Authors

Ramesh N, Pandey UB

Title

Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand.

Journal

Front Mol Neurosci 10:263 (2017)
DOI:10.3389/fnmol.2017.00263

Reference

PMID:17409386

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

Reference

PMID:17566607

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

PMID:26388731

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

Front Cell Neurosci 9:341 (2015)
DOI:10.3389/fncel.2015.00341

Reference

PMID:25991442

Authors

Menzies FM, Fleming A, Rubinsztein DC

Title

Compromised autophagy and neurodegenerative diseases.

Journal

Nat Rev Neurosci 16:345-57 (2015)
DOI:10.1038/nrn3961

Reference

PMID:32119873

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

J Mol Biol 432:2692-2713 (2020)
DOI:10.1016/j.jmb.2020.02.018

Reference

PMID:28057298

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

Curr Top Dev Biol 121:111-171 (2017)
DOI:10.1016/bs.ctdb.2016.07.004

Reference

PMID:24619348

Authors

Hetz C, Mollereau B

Title

Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases.

Journal

Nat Rev Neurosci 15:233-49 (2014)
DOI:10.1038/nrn3689

Reference

PMID:27815720

Authors

Xiang C, Wang Y, Zhang H, Han F

Title

The role of endoplasmic reticulum stress in neurodegenerative disease.

Journal

Apoptosis 22:1-26 (2017)
DOI:10.1007/s10495-016-1296-4

Reference

PMID:29476642

Authors

Hughes D, Mallucci GR

Title

The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway.

Journal

FEBS J 286:342-355 (2019)
DOI:10.1111/febs.14422

Reference

PMID:21722302

Authors

Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ, Samali A

Title

Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders.

Journal

J Cell Mol Med 15:2025-39 (2011)
DOI:10.1111/j.1582-4934.2011.01374.x

Reference

PMID:16472115

Authors

Turner BJ, Atkin JD

Title

ER stress and UPR in familial amyotrophic lateral sclerosis.

Journal

Curr Mol Med 6:79-86 (2006)
DOI:10.2174/156652406775574550

Reference

PMID:18519638

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

PMID:21834058

Authors

Walker AK, Atkin JD

Title

Stress signaling from the endoplasmic reticulum: A central player in the pathogenesis of amyotrophic lateral sclerosis.

Journal

IUBMB Life 63:754-63 (2011)
DOI:10.1002/iub.520

Reference

PMID:31319884

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

Acta Neuropathol Commun 7:103 (2019)
DOI:10.1186/s40478-019-0758-7

Reference

PMID:29605155

Authors

Nguyen HP, Van Broeckhoven C, van der Zee J

Title

ALS Genes in the Genomic Era and their Implications for FTD.

Journal

Trends Genet 34:404-423 (2018)
DOI:10.1016/j.tig.2018.03.001

Reference

PMID:25071440

Authors

Atkin G, Paulson H

Title

Ubiquitin pathways in neurodegenerative disease.

Journal

Front Mol Neurosci 7:63 (2014)
DOI:10.3389/fnmol.2014.00063

Reference

PMID:29299811

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

Neurochem Res 44:228-233 (2019)
DOI:10.1007/s11064-017-2461-z

Reference

PMID:30242016

Authors

Benarroch EE

Title

Sigma-1 receptor and amyotrophic lateral sclerosis.

Journal

Neurology 91:743-747 (2018)
DOI:10.1212/WNL.0000000000006347

Reference

PMID:23361386