Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

ALS2

  • Andrew P. Martin
  • Justin D. Topp
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101505

Synonyms

 Alsin

Historical Background

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease that leads to progressive muscle deterioration and commonly death within 3–5 years of symptom onset. The first gene established to cause ALS when mutated was SOD1, identified by a team of geneticists in 1990. Since then, more than 25 genes have been identified or implicated in ALS (Marangi and Traynor 2015). Though awareness of the genetic factors that cause ALS is impressive, clear understanding of the mechanism or mechanisms by which the known mutations trigger motor neuron degeneration is lacking. Several hypotheses have been proposed including protein aggregation, defective RNA processing, oxidative stress, subcellular organelle dysfunction, increased apoptosis, neuroinflammation, and glutamate excitotoxicity (Paez-Colsante et al. 2015). All are supported by evidence indicating there are many different potential ways by which motor neuron function can be...

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References

  1. Abiko H, Fukiwara S, Ohashi K, Hiatari R, Mashiko T, Sakamoto N, Sato M, Mizuno K. Rho-guanine nucleotide exchange factors involved in cyclic stretch-induced reorientation of vascular endothelial cells. J Cell Sci. 2015;138:1683–95.  https://doi.org/10.1242/jcs.157503.CrossRefGoogle Scholar
  2. Cai H, Shim H, Lai C, Xie C, Lin X, Yang WJ, Chandran J. ALS2/alsin knockout mice and motor neuron diseases. Neurodegener Dis. 2008;5:359–66.  https://doi.org/10.1159/000151295.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Chandran J, Ding J, Cai H. Alsin and the molecular pathways of amyotrophic lateral sclerosis. Mol Neurobiol. 2007;36:224–3.  https://doi.org/10.1007/s12035-007-0034-x.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Couthouis J, Raphael AR, Daneshjou R, Gitler AD. Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet. 2014;10:e1004704.  https://doi.org/10.1371/journal.pgen.1004704.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Devon RS, Orban PC, Gerrow K, Barbieri MA, Schwab C, Cao LP, Helm JR, Bissada N, Cruz-Aguado R, Davidson TL, Witmer J, Metzler M, Lam CK, Tetzlaff W, Simpson EM, McCaffery JM, El-Husseini AE, Leavitt BR, Hayden MR. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc Natl Acad Sci USA. 2006;103:9595–600.  https://doi.org/10.1523/JNEUROSCI.2084-06.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Gautam M, Jara JH, Sekerkova G, Yasvoina MV, Martina M, Özdinler PH. Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms. Hum Mol Genet. 2016;25:1076–87.  https://doi.org/10.1093/hmg/ddv631.CrossRefGoogle Scholar
  7. Gros-Louis F, Kriz J, Kabashi E, McDearmid J, Millecamps S, Urushitani M, Lin L, Dion P, Zhu Q, Drapeau P, Julien JP, Rouleau GA. Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish. Hum Mol Genet. 2008;17:2691–702.  https://doi.org/10.1093/hmg/ddn171.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE. Molecular and cellular function of ALS2/alsin: implication of membrane dynamics in neuronal development and degeneration. Neurochem Int. 2007;51:74–84.  https://doi.org/10.1016/j.neuint.2007.04.010.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Akatsuka A, Koike M, Aoki M, Uchiyama Y, Itoyama Y, Ikeda JE. Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1-expressing mouse ALS model by disturbing endolysosomal trafficking. PLoS One. 2010;5:e9805.  https://doi.org/10.1371/journal.pone.0009805.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Harrington AW, Ginty DD. Long-distance retrograde neurotrophic factor signalling in neurons. Nat Rev Neurosci. 2013;14:177–87.  https://doi.org/10.1038/nrn3253.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Jacquier A, Buhler E, Schäfer MK, Bohl D, Blanchard S, Beclin C, Haase G. Alsin/Rac1 signaling controls survival and growth of spinal motoneurons. Ann Neurol. 2006;60:105–17.  https://doi.org/10.1002/ana.20886.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Kanekura K, Hashimoto Y, Kita Y, Sasabe J, Aiso S, Nishimoto I, Matsuoka M. A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death. J Biol Chem. 2005;280:4534–43.  https://doi.org/10.1074/jbc.M410508200.CrossRefGoogle Scholar
  13. Kunita R, Otomo A, Mizumura H, Suzuki-Utsunomiya K, Hadano S, Ikeda JE. The Rab5 activator ALS2/alsin acts as a novel Rac1 effector through Rac1-activated endocytosis. J Biol Chem. 2007;282:16599–611.  https://doi.org/10.1074/jbc.M610682200.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lai C, Xie X, McCormack S, Chiang HS, Michalak M, Lin X, Chandran J, Shim H, Shimoji M, Cookson MR, Huganir RL, Rothstein JD, Price DL, Wong PC, Martin LJ, Zhu JJ, Cai H. Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. J Neurosci. 2006;83:186–92.  https://doi.org/10.1523/JNEUROSCI.2084-06.2006.CrossRefGoogle Scholar
  15. Marangi G, Traynor BJ. Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. Brain Res. 2015;1607:75–93.  https://doi.org/10.1016/j.brainres.2014.10.009.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Otomo A, Hadano S, Okada T, Mizumura H, Kunita R, Nishijima H, Showguchi-Miyata J, Yanagisawa Y, Kohiki E, Suga E, Yasuda M, Osuga H, Nishimoto T, Narumiya S, Ikeda JE. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003;12:1671–87.  https://doi.org/10.1093/hmg/ddg184.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Paez-Colasante X, Figueroa-Romero C, Sakowski SA, Goutman SA, Feldman EL. Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era. Nat Rev Neurol. 2015;11:226–79.  https://doi.org/10.1038/nrneurol.2015.57.CrossRefGoogle Scholar
  18. Stankiewicz TR, Linseman DA. Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration. Front Cell Neurosci. 2014;8:314.  https://doi.org/10.3389/fncel.2014.00314.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Topp JD, Gray NW, Gerard RD, Horazdovsky BF. Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. J Biol Chem. 2004;279:24612–23.  https://doi.org/10.1074/jbc.M313504200.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Topp JD. Alsin. UCSD-Nature Molecule Pages. 2015.  https://doi.org/10.6072/H0.MP.A004773.01.CrossRefGoogle Scholar
  21. Tudor EL, Perkinton MS, Schmidt A, Ackerley S, Brownlees J, Jacobsen NJ, Byers HL, Ward M, Hall A, Leigh PN, Shaw CE, McLoughlin DM, Miller CC. ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth. J Biol Chem. 2005;280:34735–40.  https://doi.org/10.1074/jbc.M506216200.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Science, Technology and MathematicsEndicott College School of Arts and SciencesBeverlyUSA