• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jnnpsycJournal of Neurology, Neurosurgery and PsychiatryCurrent TOCInstructions for authors
J Neurol Neurosurg Psychiatry. Aug 2005; 76(8): 1046–1057.
PMCID: PMC1739758

Molecular and cellular pathways of neurodegeneration in motor neurone disease

Full Text

The Full Text of this article is available as a PDF (223K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Maasilta P, Jokelainen M, Löytönen M, Sabel CE, Gatrell AC. Mortality from amyotrophic lateral sclerosis in Finland, 1986-1995. Acta Neurol Scand. 2001 Oct;104(4):232–235. [PubMed]
  • Ince PG, Tomkins J, Slade JY, Thatcher NM, Shaw PJ. Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS. J Neuropathol Exp Neurol. 1998 Oct;57(10):895–904. [PubMed]
  • Mannen T, Iwata M, Toyokura Y, Nagashima K. Preservation of a certain motoneurone group of the sacral cord in amyotrophic lateral sclerosis: its clinical significance. J Neurol Neurosurg Psychiatry. 1977 May;40(5):464–469. [PMC free article] [PubMed]
  • del Aguila MA, Longstreth WT, Jr, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology. 2003 Mar 11;60(5):813–819. [PubMed]
  • Turner MR, Parton MJ, Shaw CE, Leigh PN, Al-Chalabi A. Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990-2002. J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):995–997. [PMC free article] [PubMed]
  • Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293–299. [PubMed]
  • Hudson AJ. Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review. Brain. 1981 Jun;104(2):217–247. [PubMed]
  • Massman PJ, Sims J, Cooke N, Haverkamp LJ, Appel V, Appel SH. Prevalence and correlates of neuropsychological deficits in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1996 Nov;61(5):450–455. [PMC free article] [PubMed]
  • Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Jul 22;364(6435):362–362. [PubMed]
  • Andersen Peter M, Sims Katherine B, Xin Winnie W, Kiely Rosemary, O'Neill Gilmore, Ravits John, Pioro Erik, Harati Yadollah, Brower Richard D, Levine Johanan S, et al. Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Jun;4(2):62–73. [PubMed]
  • Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J Biol Chem. 2001 Oct 19;276(42):38388–38393. [PubMed]
  • Bruijn Lucie I, Miller Timothy M, Cleveland Don W. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004;27:723–749. [PubMed]
  • Andersen PM, Forsgren L, Binzer M, Nilsson P, Ala-Hurula V, Keränen ML, Bergmark L, Saarinen A, Haltia T, Tarvainen I, et al. Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients. Brain. 1996 Aug;119(Pt 4):1153–1172. [PubMed]
  • Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, Hayden DL, Schoenfeld DA, Hosler BA, Horvitz HR, Brown RH. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997 Feb;41(2):210–221. [PubMed]
  • Kunst CB, Messer L, Gordon J, Haines J, Patterson D. Genetic mapping of a mouse modifier gene that can prevent ALS onset. Genomics. 2000 Dec 1;70(2):181–189. [PubMed]
  • Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995 Jun;14(6):1105–1116. [PubMed]
  • Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994 Jun 17;264(5166):1772–1775. [PubMed]
  • Bruijn LI, Cleveland DW. Mechanisms of selective motor neuron death in ALS: insights from transgenic mouse models of motor neuron disease. Neuropathol Appl Neurobiol. 1996 Oct;22(5):373–387. [PubMed]
  • Nagai M, Aoki M, Miyoshi I, Kato M, Pasinelli P, Kasai N, Brown RH, Jr, Itoyama Y. Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease. J Neurosci. 2001 Dec 1;21(23):9246–9254. [PubMed]
  • Howland David S, Liu Jian, She Yijin, Goad Beth, Maragakis Nicholas J, Kim Benjamin, Erickson Jamie, Kulik John, DeVito Lisa, Psaltis George, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1604–1609. [PMC free article] [PubMed]
  • Cookson Mark R, Menzies Fiona M, Manning Philip, Eggett Christopher J, Figlewicz Denise A, McNeil Calum J, Shaw Pamela J. Cu/Zn superoxide dismutase (SOD1) mutations associated with familial amyotrophic lateral sclerosis (ALS) affect cellular free radical release in the presence of oxidative stress. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Jun;3(2):75–85. [PubMed]
  • Pasinelli P, Borchelt DR, Houseweart MK, Cleveland DW, Brown RH., Jr Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15763–15768. [PMC free article] [PubMed]
  • Roy J, Minotti S, Dong L, Figlewicz DA, Durham HD. Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by postsynaptic calcium-dependent mechanisms. J Neurosci. 1998 Dec 1;18(23):9673–9684. [PubMed]
  • Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001 Oct;29(2):166–173. [PubMed]
  • Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001 Oct;29(2):160–165. [PubMed]
  • Eymard-Pierre Eleonore, Lesca Gaetan, Dollet Sandra, Santorelli Filippo Maria, di Capua Matteo, Bertini Enrico, Boespflug-Tanguy Odile. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet. 2002 Sep;71(3):518–527. [PMC free article] [PubMed]
  • Devon RS, Helm JR, Rouleau GA, Leitner Y, Lerman-Sagie T, Lev D, Hayden MR. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. Clin Genet. 2003 Sep;64(3):210–215. [PubMed]
  • Gros-Louis François, Meijer Inge A, Hand Collette K, Dubé Marie-Pierre, MacGregor Daune L, Seni Marie-Hélène, Devon Rebecca S, Hayden Michael R, Andermann Frederick, Andermann Eva, et al. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol. 2003 Jan;53(1):144–145. [PubMed]
  • Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001 Nov 9;294(5545):1299–1304. [PubMed]
  • Yamanaka Koji, Vande Velde Christine, Eymard-Pierre Eleonore, Bertini Enrico, Boespflug-Tanguy Odile, Cleveland Don W. Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16041–16046. [PMC free article] [PubMed]
  • Otomo Asako, Hadano Shinji, Okada Takeya, Mizumura Hikaru, Kunita Ryota, Nishijima Hitoshi, Showguchi-Miyata Junko, Yanagisawa Yoshiko, Kohiki Eri, Suga Etsuko, et al. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003 Jul 15;12(14):1671–1687. [PubMed]
  • Kunita Ryota, Otomo Asako, Mizumura Hikaru, Suzuki Kyoko, Showguchi-Miyata Junko, Yanagisawa Yoshiko, Hadano Shinji, Ikeda Joh-E. Homo-oligomerization of ALS2 through its unique carboxyl-terminal regions is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking. J Biol Chem. 2004 Sep 10;279(37):38626–38635. [PubMed]
  • Bryan WW, Hoagland RJ, Murphy J, Armon C, Barohn RJ, Goodpasture JC, Miller RG, Parry GJ, Petajan JH, Ross MA, et al. Can we eliminate placebo in ALS clinical trials? Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Apr;4(1):11–15. [PubMed]
  • Bryan WW, Hoagland RJ, Murphy J, Armon C, Barohn RJ, Goodpasture JC, Miller RG, Parry GJ, Petajan JH, Ross MA, et al. Can we eliminate placebo in ALS clinical trials? Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Apr;4(1):11–15. [PubMed]
  • Kanekura Kohsuke, Hashimoto Yuichi, Niikura Takako, Aiso Sadakazu, Matsuoka Masaaki, Nishimoto Ikuo. Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants. J Biol Chem. 2004 Apr 30;279(18):19247–19256. [PubMed]
  • Chen Ying-Zhang, Bennett Craig L, Huynh Huy M, Blair Ian P, Puls Imke, Irobi Joy, Dierick Ines, Abel Annette, Kennerson Marina L, Rabin Bruce A, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128–1135. [PMC free article] [PubMed]
  • Moreira Maria-Céu, Klur Sandra, Watanabe Mitsunori, Németh Andrea H, Le Ber Isabelle, Moniz José-Carlos, Tranchant Christine, Aubourg Patrick, Tazir Meriem, Schöls Lüdger, et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet. 2004 Mar;36(3):225–227. [PubMed]
  • Nishimura Agnes L, Mitne-Neto Miguel, Silva Helga C A, Richieri-Costa Antônio, Middleton Susan, Cascio Duilio, Kok Fernando, Oliveira João R M, Gillingwater Tom, Webb Jeanette, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Nov;75(5):822–831. [PMC free article] [PubMed]
  • Puls Imke, Jonnakuty Catherine, LaMonte Bernadette H, Holzbaur Erika L F, Tokito Mariko, Mann Eric, Floeter Mary Kay, Bidus Kimberly, Drayna Dennis, Oh Shin J, et al. Mutant dynactin in motor neuron disease. Nat Genet. 2003 Apr;33(4):455–456. [PubMed]
  • LaMonte Bernadette H, Wallace Karen E, Holloway Beth A, Shelly Spencer S, Ascaño Jennifer, Tokito Mariko, Van Winkle Thomas, Howland David S, Holzbaur Erika L F. Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron. 2002 May 30;34(5):715–727. [PubMed]
  • Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, Daube JR, Nance M, Fan C, Kaplan J, et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA. 2000 Oct 4;284(13):1664–1669. [PubMed]
  • Ostojic Jovanka, Axelman Karin, Lannfelt Lars, Froelich-Fabre Susanne. No evidence of linkage to chromosome 9q21-22 in a Swedish family with frontotemporal dementia and amyotrophic lateral sclerosis. Neurosci Lett. 2003 Apr 17;340(3):245–247. [PubMed]
  • Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, et al. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13103–13107. [PMC free article] [PubMed]
  • Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702–705. [PubMed]
  • Kowalska Anna, Konagaya Masaaki, Sakai Motoko, Hashizume Yoshio, Tabira Takeshi. Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex--tauopathy without mutations in the tau gene? Folia Neuropathol. 2003;41(2):59–64. [PubMed]
  • Wilhelmsen Kirk C, Forman Mark S, Rosen Howard J, Alving Loren I, Goldman Jill, Feiger Jennie, Lee James V, Segall Samantha K, Kramer Joel H, Lomen-Hoerth Catherine, et al. 17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau mutations with tau and alpha-synuclein inclusions. Arch Neurol. 2004 Mar;61(3):398–406. [PubMed]
  • Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien JP. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet. 1994 Oct;3(10):1757–1761. [PubMed]
  • Tomkins J, Usher P, Slade JY, Ince PG, Curtis A, Bushby K, Shaw PJ. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport. 1998 Dec 1;9(17):3967–3970. [PubMed]
  • al-Chalabi A, Enayat ZE, Bakker MC, Sham PC, Ball DM, Shaw CE, Lloyd CM, Powell JF, Leigh PN. Association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease. Lancet. 1996 Jan 20;347(8995):159–160. [PubMed]
  • Drory VE, Birnbaum M, Korczyn AD, Chapman J. Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis. J Neurol Sci. 2001 Sep 15;190(1-2):17–20. [PubMed]
  • Comi GP, Bordoni A, Salani S, Franceschina L, Sciacco M, Prelle A, Fortunato F, Zeviani M, Napoli L, Bresolin N, et al. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann Neurol. 1998 Jan;43(1):110–116. [PubMed]
  • Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995 Jul;38(1):73–84. [PubMed]
  • Rao Shyam D, Yin Hong Z, Weiss John H. Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons. J Neurosci. 2003 Apr 1;23(7):2627–2633. [PubMed]
  • Fray AE, Ince PG, Banner SJ, Milton ID, Usher PA, Cookson MR, Shaw PJ. The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci. 1998 Aug;10(8):2481–2489. [PubMed]
  • Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron. 1998 Mar;20(3):589–602. [PubMed]
  • Meyer T, Fromm A, Münch C, Schwalenstöcker B, Fray AE, Ince PG, Stamm S, Grön G, Ludolph AC, Shaw PJ. The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals. J Neurol Sci. 1999 Nov 15;170(1):45–50. [PubMed]
  • Flowers JM, Powell JF, Leigh PN, Andersen P, Shaw CE. Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis. Ann Neurol. 2001 May;49(5):643–649. [PubMed]
  • Trotti D, Aoki M, Pasinelli P, Berger UV, Danbolt NC, Brown RH, Jr, Hediger MA. Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity. J Biol Chem. 2001 Jan 5;276(1):576–582. [PubMed]
  • Kawahara Yukio, Ito Kyoko, Sun Hui, Aizawa Hitoshi, Kanazawa Ichiro, Kwak Shin. Glutamate receptors: RNA editing and death of motor neurons. Nature. 2004 Feb 26;427(6977):801–801. [PubMed]
  • Jackson M, Morrison KE, Al-Chalabi A, Bakker M, Leigh PN. Analysis of chromosome 5q13 genes in amyotrophic lateral sclerosis: homozygous NAIP deletion in a sporadic case. Ann Neurol. 1996 Jun;39(6):796–800. [PubMed]
  • Orrell RW, Habgood JJ, de Belleroche JS, Lane RJ. The relationship of spinal muscular atrophy to motor neuron disease: investigation of SMN and NAIP gene deletions in sporadic and familial ALS. J Neurol Sci. 1997 Jan;145(1):55–61. [PubMed]
  • Veldink JH, van den Berg LH, Cobben JM, Stulp RP, De Jong JM, Vogels OJ, Baas F, Wokke JH, Scheffer H. Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS. Neurology. 2001 Mar 27;56(6):749–752. [PubMed]
  • Corcia Philippe, Mayeux-Portas Véronique, Khoris Jawad, de Toffol Bertrand, Autret Alain, Müh Jean-Pierre, Camu William, Andres Christian. Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis. Ann Neurol. 2002 Feb;51(2):243–246. [PubMed]
  • Giess Ralf, Holtmann Bettina, Braga Massimiliano, Grimm Tiemo, Müller-Myhsok Bertram, Toyka Klaus V, Sendtner Michael. Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene. Am J Hum Genet. 2002 May;70(5):1277–1286. [PMC free article] [PubMed]
  • Brockington A, Lewis C, Wharton S, Shaw PJ. Vascular endothelial growth factor and the nervous system. Neuropathol Appl Neurobiol. 2004 Oct;30(5):427–446. [PubMed]
  • Lambrechts Diether, Storkebaum Erik, Morimoto Masafumi, Del-Favero Jurgen, Desmet Frederik, Marklund Stefan L, Wyns Sabine, Thijs Vincent, Andersson Jörgen, van Marion Ingrid, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003 Aug;34(4):383–394. [PubMed]
  • Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001 Jun;28(2):131–138. [PubMed]
  • Gros-Louis Francois, Laurent Sandra, Lopes Ana Amelia Simões, Khoris Jawad, Meininger Vincent, Camu William, Rouleau Guy A. Absence of mutations in the hypoxia response element of VEGF in ALS. Muscle Nerve. 2003 Dec;28(6):774–775. [PubMed]
  • Shaw PJ, Ince PG, Falkous G, Mantle D. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol. 1995 Oct;38(4):691–695. [PubMed]
  • Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, Kowall NW, Brown RH, Jr, Beal MF. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997 Nov;69(5):2064–2074. [PubMed]
  • Smith RG, Henry YK, Mattson MP, Appel SH. Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Ann Neurol. 1998 Oct;44(4):696–699. [PubMed]
  • Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, Isobe C. Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis. Ann Neurol. 1999 Jul;46(1):129–131. [PubMed]
  • Aguirre T, Van Den Bosch L, Goetschalckx K, Tilkin P, Mathijs G, Cassiman JJ, Robberecht W. Increased sensitivity of fibroblasts from amyotrophic lateral sclerosis patients to oxidative stress. Ann Neurol. 1998 Apr;43(4):452–457. [PubMed]
  • Beckman JS, Carson M, Smith CD, Koppenol WH. ALS, SOD and peroxynitrite. Nature. 1993 Aug 12;364(6438):584–584. [PubMed]
  • Crow JP, Sampson JB, Zhuang Y, Thompson JA, Beckman JS. Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem. 1997 Nov;69(5):1936–1944. [PubMed]
  • Estévez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, Richardson GJ, Tarpey MM, Barbeito L, Beckman JS. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science. 1999 Dec 24;286(5449):2498–2500. [PubMed]
  • Wang Jiou, Slunt Hilda, Gonzales Victoria, Fromholt David, Coonfield Michael, Copeland Neal G, Jenkins Nancy A, Borchelt David R. Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature. Hum Mol Genet. 2003 Nov 1;12(21):2753–2764. [PubMed]
  • Subramaniam Jamuna R, Lyons W Ernest, Liu Jian, Bartnikas Thomas B, Rothstein Jeffrey, Price Donald L, Cleveland Don W, Gitlin Jonathan D, Wong Philip C. Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat Neurosci. 2002 Apr;5(4):301–307. [PubMed]
  • Facchinetti F, Sasaki M, Cutting FB, Zhai P, MacDonald JE, Reif D, Beal MF, Huang PL, Dawson TM, Gurney ME, et al. Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis. Neuroscience. 1999;90(4):1483–1492. [PubMed]
  • Upton-Rice MN, Cudkowicz ME, Mathew RK, Reif D, Brown RH., Jr Administration of nitric oxide synthase inhibitors does not alter disease course of amyotrophic lateral sclerosis SOD1 mutant transgenic mice. Ann Neurol. 1999 Mar;45(3):413–414. [PubMed]
  • Son M, Fathallah-Shaykh HM, Elliott JL. Survival in a transgenic model of FALS is independent of iNOS expression. Ann Neurol. 2001 Aug;50(2):273–273. [PubMed]
  • Carriedo SG, Yin HZ, Weiss JH. Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J Neurosci. 1996 Jul 1;16(13):4069–4079. [PubMed]
  • Heath Paul R, Shaw Pamela J. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve. 2002 Oct;26(4):438–458. [PubMed]
  • Shaw PJ, Forrest V, Ince PG, Richardson JP, Wastell HJ. CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration. 1995 Jun;4(2):209–216. [PubMed]
  • Spreux-Varoquaux Odile, Bensimon Gilbert, Lacomblez Lucette, Salachas François, Pradat Pierre François, Le Forestier Nadine, Marouan Abdellatif, Dib Michel, Meininger Vincent. Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J Neurol Sci. 2002 Jan 15;193(2):73–78. [PubMed]
  • Kruman II, Pedersen WA, Springer JE, Mattson MP. ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. Exp Neurol. 1999 Nov;160(1):28–39. [PubMed]
  • Spalloni Alida, Albo Federica, Ferrari Francesca, Mercuri Nicola, Bernardi Giorgio, Zona Cristina, Longone Patrizia. Cu/Zn-superoxide dismutase (GLY93-->ALA) mutation alters AMPA receptor subunit expression and function and potentiates kainate-mediated toxicity in motor neurons in culture. Neurobiol Dis. 2004 Mar;15(2):340–350. [PubMed]
  • Bendotti C, Tortarolo M, Suchak SK, Calvaresi N, Carvelli L, Bastone A, Rizzi M, Rattray M, Mennini T. Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J Neurochem. 2001 Nov;79(4):737–746. [PubMed]
  • Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996 May 25;347(9013):1425–1431. [PubMed]
  • Gurney ME, Cutting FB, Zhai P, Doble A, Taylor CP, Andrus PK, Hall ED. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 1996 Feb;39(2):147–157. [PubMed]
  • Beal MF. Mitochondria and the pathogenesis of ALS. Brain. 2000 Jul;123(Pt 7):1291–1292. [PubMed]
  • Menzies Fiona M, Ince Paul G, Shaw Pamela J. Mitochondrial involvement in amyotrophic lateral sclerosis. Neurochem Int. 2002 May;40(6):543–551. [PubMed]
  • Siklós L, Engelhardt J, Harati Y, Smith RG, Joó F, Appel SH. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis. Ann Neurol. 1996 Feb;39(2):203–216. [PubMed]
  • Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol. 1999 Nov;46(5):787–790. [PubMed]
  • Dhaliwal GK, Grewal RP. Mitochondrial DNA deletion mutation levels are elevated in ALS brains. Neuroreport. 2000 Aug 3;11(11):2507–2509. [PubMed]
  • Wiedemann Falk R, Manfredi Giovanni, Mawrin Christian, Beal M Flint, Schon Eric A. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem. 2002 Feb;80(4):616–625. [PubMed]
  • Menzies Fiona M, Cookson Mark R, Taylor Robert W, Turnbull Douglass M, Chrzanowska-Lightowlers Zofia M A, Dong Lichun, Figlewicz Denise A, Shaw Pamela J. Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain. 2002 Jul;125(Pt 7):1522–1533. [PubMed]
  • Fukada Kei, Zhang Fujian, Vien Alexis, Cashman Neil R, Zhu Haining. Mitochondrial proteomic analysis of a cell line model of familial amyotrophic lateral sclerosis. Mol Cell Proteomics. 2004 Dec;3(12):1211–1223. [PMC free article] [PubMed]
  • Takeuchi Hideyuki, Kobayashi Yasushi, Ishigaki Shinsuke, Doyu Manabu, Sobue Gen. Mitochondrial localization of mutant superoxide dismutase 1 triggers caspase-dependent cell death in a cellular model of familial amyotrophic lateral sclerosis. J Biol Chem. 2002 Dec 27;277(52):50966–50972. [PubMed]
  • Higgins Cynthia M J, Jung Cheolwha, Ding Hongliu, Xu Zuoshang. Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J Neurosci. 2002 Mar 15;22(6):RC215–RC215. [PubMed]
  • Jaarsma D, Rognoni F, van Duijn W, Verspaget HW, Haasdijk ED, Holstege JC. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. 2001 Oct;102(4):293–305. [PubMed]
  • Jung Cheolwha, Higgins Cynthia M J, Xu Zuoshang. A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sections. J Neurosci Methods. 2002 Mar 15;114(2):165–172. [PubMed]
  • Mattiazzi Marina, D'Aurelio Marilena, Gajewski Carl D, Martushova Katherine, Kiaei Mahmoud, Beal M Flint, Manfredi Giovanni. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J Biol Chem. 2002 Aug 16;277(33):29626–29633. [PubMed]
  • Guégan C, Vila M, Rosoklija G, Hays AP, Przedborski S. Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis. J Neurosci. 2001 Sep 1;21(17):6569–6576. [PubMed]
  • Zhu Shan, Stavrovskaya Irina G, Drozda Martin, Kim Betty Y S, Ona Victor, Li Mingwei, Sarang Satinder, Liu Allen S, Hartley Dean M, Wu Du Chu, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002 May 2;417(6884):74–78. [PubMed]
  • Andreassen OA, Ferrante RJ, Klivenyi P, Klein AM, Shinobu LA, Epstein CJ, Beal MF. Partial deficiency of manganese superoxide dismutase exacerbates a transgenic mouse model of amyotrophic lateral sclerosis. Ann Neurol. 2000 Apr;47(4):447–455. [PubMed]
  • Liu Jian, Lillo Concepción, Jonsson P Andreas, Vande Velde Christine, Ward Christopher M, Miller Timothy M, Subramaniam Jamuna R, Rothstein Jeffery D, Marklund Stefan, Andersen Peter M, et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron. 2004 Jul 8;43(1):5–17. [PubMed]
  • Pasinelli Piera, Belford Mary Elizabeth, Lennon Niall, Bacskai Brian J, Hyman Bradley T, Trotti Davide, Brown Robert H., Jr Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004 Jul 8;43(1):19–30. [PubMed]
  • Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal MF. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med. 1999 Mar;5(3):347–350. [PubMed]
  • Xu Z, Cork LC, Griffin JW, Cleveland DW. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell. 1993 Apr 9;73(1):23–33. [PubMed]
  • Côté F, Collard JF, Julien JP. Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell. 1993 Apr 9;73(1):35–46. [PubMed]
  • Lee MK, Marszalek JR, Cleveland DW. A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron. 1994 Oct;13(4):975–988. [PubMed]
  • Tu PH, Raju P, Robinson KA, Gurney ME, Trojanowski JQ, Lee VM. Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3155–3160. [PMC free article] [PubMed]
  • Zhang B, Tu P, Abtahian F, Trojanowski JQ, Lee VM. Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol. 1997 Dec 1;139(5):1307–1315. [PMC free article] [PubMed]
  • Couillard-Després S, Zhu Q, Wong PC, Price DL, Cleveland DW, Julien JP. Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9626–9630. [PMC free article] [PubMed]
  • Beaulieu JM, Nguyen MD, Julien JP. Late onset of motor neurons in mice overexpressing wild-type peripherin. J Cell Biol. 1999 Nov 1;147(3):531–544. [PMC free article] [PubMed]
  • Robertson Janice, Doroudchi Mohammad M, Nguyen Minh Dang, Durham Heather D, Strong Michael J, Shaw Gerry, Julien Jean-Pierre, Mushynski Walter E. A neurotoxic peripherin splice variant in a mouse model of ALS. J Cell Biol. 2003 Mar 17;160(6):939–949. [PMC free article] [PubMed]
  • Larivière Roxanne C, Beaulieu Jean-Martin, Nguyen Minh Dang, Julien Jean-Pierre. Peripherin is not a contributing factor to motor neuron disease in a mouse model of amyotrophic lateral sclerosis caused by mutant superoxide dismutase. Neurobiol Dis. 2003 Jul;13(2):158–166. [PubMed]
  • Williamson TL, Cleveland DW. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci. 1999 Jan;2(1):50–56. [PubMed]
  • Reid Evan, Kloos Mark, Ashley-Koch Allison, Hughes Lori, Bevan Simon, Svenson Ingrid K, Graham Felicia Lennon, Gaskell Perry C, Dearlove Andrew, Pericak-Vance Margaret A, et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet. 2002 Nov;71(5):1189–1194. [PMC free article] [PubMed]
  • Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, et al. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell. 2001 Jun 1;105(5):587–597. [PubMed]
  • Hafezparast Majid, Klocke Rainer, Ruhrberg Christiana, Marquardt Andreas, Ahmad-Annuar Azlina, Bowen Samantha, Lalli Giovanna, Witherden Abi S, Hummerich Holger, Nicholson Sharon, et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science. 2003 May 2;300(5620):808–812. [PubMed]
  • Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD. Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis. 2001 Dec;8(6):933–941. [PubMed]
  • Bruening W, Roy J, Giasson B, Figlewicz DA, Mushynski WE, Durham HD. Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis. J Neurochem. 1999 Feb;72(2):693–699. [PubMed]
  • Allen Simon, Heath Paul Roy, Kirby Janine, Wharton Stephen Barrie, Cookson Mark Robert, Menzies Fiona Mhairi, Banks Rosamonde Elizabeth, Shaw Pamela Jean. Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant defenses, and nitric oxide synthetic pathways. J Biol Chem. 2003 Feb 21;278(8):6371–6383. [PubMed]
  • Johnston JA, Dalton MJ, Gurney ME, Kopito RR. Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12571–12576. [PMC free article] [PubMed]
  • Takeuchi Hideyuki, Kobayashi Yasushi, Yoshihara Tsuyoshi, Niwa Jun-ichi, Doyu Manabu, Ohtsuka Kenzo, Sobue Gen. Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1. Brain Res. 2002 Sep 13;949(1-2):11–22. [PubMed]
  • Kieran Dairin, Kalmar Bernadett, Dick James R T, Riddoch-Contreras Joanna, Burnstock Geoffrey, Greensmith Linda. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med. 2004 Apr;10(4):402–405. [PubMed]
  • Pramatarova A, Laganière J, Roussel J, Brisebois K, Rouleau GA. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci. 2001 May 15;21(10):3369–3374. [PubMed]
  • Lino Maria Maddalena, Schneider Corinna, Caroni Pico. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neurosci. 2002 Jun 15;22(12):4825–4832. [PubMed]
  • Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillée S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science. 2003 Oct 3;302(5642):113–117. [PubMed]
  • González-Scarano F, Baltuch G. Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci. 1999;22:219–240. [PubMed]
  • Alexianu ME, Kozovska M, Appel SH. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology. 2001 Oct 9;57(7):1282–1289. [PubMed]
  • Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992 Mar;140(3):691–707. [PMC free article] [PubMed]
  • Sekizawa T, Openshaw H, Ohbo K, Sugamura K, Itoyama Y, Niland JC. Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases. J Neurol Sci. 1998 Feb 5;154(2):194–199. [PubMed]
  • Hensley Kenneth, Floyd Robert A, Gordon Brian, Mou Shenyun, Pye Quentin N, Stewart Charles, West Melinda, Williamson Kelly. Temporal patterns of cytokine and apoptosis-related gene expression in spinal cords of the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. J Neurochem. 2002 Jul;82(2):365–374. [PubMed]
  • Almer G, Teismann P, Stevic Z, Halaschek-Wiener J, Deecke L, Kostic V, Przedborski S. Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients. Neurology. 2002 Apr 23;58(8):1277–1279. [PubMed]
  • Elliott JL. Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis. Brain Res Mol Brain Res. 2001 Nov 1;95(1-2):172–178. [PubMed]
  • Tikka Tiina M, Vartiainen Nina E, Goldsteins Gundars, Oja Simo S, Andersen Peter M, Marklund Stefan L, Koistinaho Jari. Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain. 2002 Apr;125(Pt 4):722–731. [PubMed]
  • Zhang Wenhua, Narayanan Malini, Friedlander Robert M. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003 Feb;53(2):267–270. [PubMed]
  • Brooks BR, Shodis KA, Lewis DH, Rawling JD, Sanjak M, Belden DS, Hakim H, DeTan Y, Gaffney JM. Natural history of amyotrophic lateral sclerosis. Quantification of symptoms, signs, strength, and function. Adv Neurol. 1995;68:163–184. [PubMed]
  • Sathasivam S, Ince PG, Shaw PJ. Apoptosis in amyotrophic lateral sclerosis: a review of the evidence. Neuropathol Appl Neurobiol. 2001 Aug;27(4):257–274. [PubMed]
  • Guégan Christelle, Przedborski Serge. Programmed cell death in amyotrophic lateral sclerosis. J Clin Invest. 2003 Jan;111(2):153–161. [PMC free article] [PubMed]
  • Martin LJ. Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol. 1999 May;58(5):459–471. [PubMed]
  • Mu X, He J, Anderson DW, Trojanowski JQ, Springer JE. Altered expression of bcl-2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons. Ann Neurol. 1996 Sep;40(3):379–386. [PubMed]
  • Li M, Ona VO, Guégan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 2000 Apr 14;288(5464):335–339. [PubMed]
  • Vukosavic S, Dubois-Dauphin M, Romero N, Przedborski S. Bax and Bcl-2 interaction in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem. 1999 Dec;73(6):2460–2468. [PubMed]
  • Shaw PJ, Eggett CJ. Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol. 2000 Mar;247 (Suppl 1):I17–I27. [PubMed]
  • Williams TL, Day NC, Ince PG, Kamboj RK, Shaw PJ. Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Ann Neurol. 1997 Aug;42(2):200–207. [PubMed]
  • Ince P, Stout N, Shaw P, Slade J, Hunziker W, Heizmann CW, Baimbridge KG. Parvalbumin and calbindin D-28k in the human motor system and in motor neuron disease. Neuropathol Appl Neurobiol. 1993 Aug;19(4):291–299. [PubMed]
  • Sullivan Patrick G, Rabchevsky Alexander G, Keller Jeffery N, Lovell Mark, Sodhi Ajeet, Hart Ronald P, Scheff Stephen W. Intrinsic differences in brain and spinal cord mitochondria: Implication for therapeutic interventions. J Comp Neurol. 2004 Jul 5;474(4):524–534. [PubMed]
  • Olsen MK, Roberds SL, Ellerbrock BR, Fleck TJ, McKinley DK, Gurney ME. Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord. Ann Neurol. 2001 Dec;50(6):730–740. [PubMed]
  • Heath PR, Tomkins J, Ince PG, Shaw PJ. Quantitative assessment of AMPA receptor mRNA in human spinal motor neurons isolated by laser capture microdissection. Neuroreport. 2002 Oct 7;13(14):1753–1757. [PubMed]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...