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Het onderzoek naar ALS in een stroomversnelling?
Caroline
Eykens
LEUVEN - ‘Wat wanneer amyotrofe laterale sclerose (ALS) je lichaam binnensluipt?’. Met deze slogan kreeg de zenuwspierziekte ALS de jongste maanden heel wat media-aandacht. Het antwoord is helaas niet erg hoopgevend. De aandoening is doorgaans fataal 2 à 5 jaar na diagnose aangezien er nog geen doeltreffende therapie beschikbaar is. Wat is nu de precieze oorzaak van ALS? Dat houdt het biomedisch onderzoek al ettelijke jaren bezig. Een eenduidige verklaring hiervoor heeft men echter nog niet gevonden. In deze scriptie vestigden we de aandacht op cellen die belangrijk zijn voor de ondersteuning van de motorische zenuwcellen, meer bepaald de oligodendrocyten. Wat is er aan de hand met deze oligodendrocyten bij ALS?
ALS is een ongeneeslijke aandoening die gekenmerkt wordt door het selectief afsterven van de motorische zenuwcellen. Deze cellen zijn een belangrijke schakel in het overbrengen van commando’s van de hersenen naar de spieren. Ze zorgen ervoor dat onze spieren samentrekken wanneer actie ondernomen moet worden en verslappen in rust. Bijgevolg krijgen lijders aan de ziekte te maken met spierzwakte, onwillekeurige spierbewegingen en verlamming. ALS steekt meestal de kop op rond de leeftijd van 50 à 60 jaar en kan eender wie overkomen. De enige hulp die de medische wereld kan bieden, zijn middelen om de levenskwaliteit min of meer intact te houden tijdens het vreselijke aftakelingsproces. Uiteindelijk sterven de meeste patiënten enkele jaren na diagnose aan verstikking doordat de ademhalingsspieren verlamd raken. Door de sterk toegenomen levensverwachting en de hieruit voortvloeiende toename van een oudere bevolking, wordt onze samenleving alsmaar meer geconfronteerd met ALS. Hierdoor komen zorginstellingen onder druk te staan, maar ook de patiënten zelf en hun omgeving moeten heel wat leed verwerken. Daarom onderstrepen we hier het belang van neurobiologisch onderzoek in het vinden van nieuwe therapeutische aanknopingspunten voor deze ziekte.
Muizen dragen hun steentje bij
Wereldwijd worden ALS-muizen ingezet als laboratoriumdieren met het oog op het verrichten van neurobiologisch onderzoek. Hiermee kan men namelijk meer inzicht verwerven in het ziektemechanisme dat aan de basis ligt van ALS. Deze muizen dragen net zoals sommige ALS-patiënten een erfelijke afwijking in het SOD1 gen. Door deze afwijking in het DNA sterven de motorische zenuwcellen geleidelijk aan af. Dat leidt zowel bij de patiënt als in het muismodel tot verlamming en uiteindelijk tot de dood. Studies hebben aangetoond dat alleen maar de aanwezigheid van het afwijkende SOD1 eiwit in de motorische zenuwcellen niet voldoende is om ALS te ontwikkelen. Tegelijk moet het eiwit ook aanwezig zijn in niet-neuronale cellen zoals astrocyten, microgliale cellen, oligodendrocyt voorlopercellen en oligodendrocyten (Figuur 1, bijlage).
Antennefunctie
Bij ALS-muizen en ALS-patiënten sterven de oligodendrocyten af nog voor de ziekte doorbreekt. Oligodendrocyten zijn zenuwcellen met een dubbele functie. Enerzijds voorzien ze de zenuwuitlopers van een vetachtig omhulsel en verzekeren ze op deze manier een snelle prikkelgeleiding doorheen het centraal zenuwstelsel (Figuur 2 (①), bijlage). Anderzijds bevoorraden ze de motorische zenuwcellen met de nodige voedingsstoffen via transportertjes (Figuur 2 (②), bijlage). De afgestorven oligodendrocyten worden vervangen door nieuwe oligodendrocyten, maar bij ALS werken deze niet zoals het hoort. Aangezien oligodendrocyten niet kunnen delen, worden de nieuwe oligodendrocyten gevormd uit een reservoir van voorlopercellen (Figuur 3, bijlage). De Notch-1 receptor, vergelijkbaar met een soort antenne op de cel die signalen ontvangt en verzendt, is aanwezig op deze voorlopercellen. Men vermoedt dat deze receptor de uitgroei van oligodendrocyt voorlopercellen tot volwassen oligodendrocyten verhindert. Daarom vroegen we ons af of een ontregeling van de Notch-1 receptor bijdraagt tot de slechte uitgroei van de oligodendrocyt voorlopercellen bij ALS. Om deze hypothese te staven, onderzochten we of de verwijdering van de Notch-1 receptor bij ALS-muizen een gunstig effect zou kunnen hebben op het ziekteproces.
Weg met Notch-1
We weten dus dat bij ALS de oligodendrocyten niet goed werken. Zal verwijdering van de Notch-1 receptor de functie van deze cellen verbeteren? Onderzoek wees uit dat ALS-muizen met een gedaalde hoeveelheid van de Notch-1 receptor, een stijging van MBP en MCT-1 vertoonden in het ruggenmerg, in vergelijking met de ALS-muizen waarin de receptor normaal aanwezig was (Figuur 4, bijlage). Vermits beide eiwitten een idee geven over de werking van de oligodendrocyten, wijst deze waarneming op een betere werking van de oligodendrocyten na Notch-1 verwijdering bij ALS.
Het eerste belangrijke symptoom in het ziekteverloop van ALS is dat de uitlopers van de motorische zenuwcellen zich terugtrekken uit de spier die ze bezenuwen. Kan Notch-1 verwijdering dat tegengaan? Onze resultaten suggereren van wel. Bij ALS-muizen waarin de Notch-1 receptor zo goed als afwezig was, maakte een groter aantal uitlopers van de motorische zenuwcellen contact met de kuitspier in vergelijking met gewone ALS-muizen (Figuur 5, bijlage). Dat werd ook vertaald in een betere prikkelgeleiding in de spier, zoals we konden waarnemen in de resultaten van onze elektromyografie (Figuur 6, bijlage). Hierbij wordt het principe van vraag en antwoord toegepast. De motorische zenuwcellen krijgen een elektrische schok toegediend en er wordt gemeten hoe groot de reactie van de spier hierop is (Figuur 7, bijlage).
Ziekte afremmen
Samengevat kunnen we stellen dat verwijdering van de Notch-1 receptor de werking van de oligodendrocyten verbetert bij ALS. Ook de communicatie tussen de motorische zenuwcellen en de spiervezels verloopt efficiënter. De Notch-1 receptor zou dus een mogelijk therapeutisch aangrijpingspunt kunnen vormen in de strijd tegen deze vreselijke aandoening. Met deze ontdekking kunnen we ALS waarschijnlijk niet genezen, maar het geeft ons wel de mogelijkheid om de ziekte trachten af te remmen. Notch-1 is een fascinerende receptor die ons weer een stapje verder helpt in het neurobiologisch onderzoek naar ALS.
‘‘Verwijdering van de Notch-1 receptor heeft een gunstig effect op het ziekteverloop van ALS. Hopelijk kan deze ontdekking bijdragen tot het afremmen van deze ziekte’’
- Heeft u na het lezen van dit artikel meer interesse gekregen in het huidige onderwerp? Dan is het zeker aan te raden om de integrale thesis ‘Notch-1 signaaltransductie en oligodendrocyten dysfunctie in amyotrofe laterale sclerose’ te lezen. Deze werd bekroond met de eerste prijs voor de ’Beste masterproef biomedische wetenschappen 2013’(KU Leuven).
Caroline EYKENS
Bibliografie
1. Hayashi S, McMahon AP. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol. 2002 Apr 15;244(2):305-18.
2. Cleveland DW, Rothstein JD. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci. 2001 Nov;2(11):806-19.
3. Lee AG. Myelin: Delivery by raft. Curr Biol. 2001 Jan 23;11(2):R60-2.
4. Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006 Oct 5;52(1):39-59.
5. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001 May 31;344(22):1688-700.
6. Mulder DW, Kurland LT, Offord KP, Beard CM. Familial adult motor neuron disease: amyotrophic lateral sclerosis. Neurology. 1986 Apr;36(4):511-7.
7. Hugon J. Riluzole and ALS therapy. Wien Med Wochenschr. 1996;146(9-10):185-7.
8. Gordon PH. Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management. CNS Drugs. 2011 Jan;25(1):1-15.
9. Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004;27:723-49.
10. Andersen PM, Nilsson P, Keranen ML, Forsgren L, Hagglund J, Karlsborg M, et al. Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain. 1997 Oct;120 ( Pt 10):1723-37.
11. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011 Nov;7(11):603-15.
12. Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Jul 22;364(6435):362.
13. Andersen PM. The genetics of amyotrophic lateral sclerosis (ALS). Suppl Clin Neurophysiol. 2004;57:211-27.
14. Andersen PM, Nilsson P, Ala-Hurula V, Keranen ML, Tarvainen I, Haltia T, et al. Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase. Nat Genet. 1995 May;10(1):61-6.
15. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet. 1996 May;13(1):43-7.
16. Daoud H, Valdmanis PN, Kabashi E, Dion P, Dupre N, Camu W, et al. Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis. J Med Genet. 2009 Feb;46(2):112-4.
17. Chio A, Borghero G, Pugliatti M, Ticca A, Calvo A, Moglia C, et al. Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene. Arch Neurol. 2011 May;68(5):594-8.
18. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3.
19. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208-11.
20. Tsai CP, Soong BW, Lin KP, Tu PH, Lin JL, Lee YC. FUS, TARDBP, and SOD1 mutations in a Taiwanese cohort with familial ALS. Neurobiol Aging. 2011 Mar;32(3):553 e13-21.
21. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20;72(2):245-56.
22. van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, Engelborghs S, et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat. 2013 Feb;34(2):363-73.
23. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012 Apr;11(4):323-30.
24. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012 Jan;11(1):54-65.
25. Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):260-5.
26. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013 Apr;14(4):248-64.
27. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994 Jun 17;264(5166):1772-5.
28. Shibata N. Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Neuropathology. 2001 Mar;21(1):82-92.
29. Prudencio M, Hart PJ, Borchelt DR, Andersen PM. Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. Hum Mol Genet. 2009 Sep 1;18(17):3217-26.
30. Shibata N, Hirano A, Yamamoto T, Kato Y, Kobayashi M. Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):143-61.
31. Ilieva H, Polymenidou M, Cleveland DW. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009 Dec 14;187(6):761-72.
32. Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009 Jan;65 Suppl 1:S3-9.
33. 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:I17-27.
34. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 2004 Sep 15;37(6):755-67.
35. Lambert AJ, Brand MD. Reactive oxygen species production by mitochondria. Methods Mol Biol. 2009;554:165-81.
36. Barber SC, Mead RJ, Shaw PJ. Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1051-67.
37. Pardo CA, Xu Z, Borchelt DR, Price DL, Sisodia SS, Cleveland DW. Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):954-8.
38. Quaegebeur A, Carmeliet P. Oxygen sensing: a common crossroad in cancer and neurodegeneration. Curr Top Microbiol Immunol. 2010;345:71-103.
39. Yim MB, Kang JH, Yim HS, Kwak HS, Chock PB, Stadtman ER. A gain-of-function of an amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutant: An enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5709-14.
40. Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science. 1993 Aug 20;261(5124):1047-51.
41. Yim MB, Chock PB, Stadtman ER. Copper, zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5006-10.
42. Wang J, Slunt H, Gonzales V, Fromholt D, Coonfield M, Copeland NG, et al. 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):2753-64.
43. 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.
44. Shibata N, Hirano A, Kobayashi M, Dal Canto MC, Gurney ME, Komori T, et al. Presence of Cu/Zn superoxide dismutase (SOD) immunoreactivity in neuronal hyaline inclusions in spinal cords from mice carrying a transgene for Gly93Ala mutant human Cu/Zn SOD. Acta Neuropathol. 1998 Feb;95(2):136-42.
45. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997 Feb;18(2):327-38.
46. 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):12571-6.
47. Wang J, Xu G, Gonzales V, Coonfield M, Fromholt D, Copeland NG, et al. Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol Dis. 2002 Jul;10(2):128-38.
48. 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):693-9.
49. Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science. 1998 Sep 18;281(5384):1851-4.
50. Niwa J, Ishigaki S, Hishikawa N, Yamamoto M, Doyu M, Murata S, et al. Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. J Biol Chem. 2002 Sep 27;277(39):36793-8.
51. 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):933-41.
52. Rothstein JD, Kuncl R, Chaudhry V, Clawson L, Cornblath DR, Coyle JT, et al. Excitatory amino acids in amyotrophic lateral sclerosis: an update. Ann Neurol. 1991 Aug;30(2):224-5.
53. Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol. 1990 Jul;28(1):18-25.
54. 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):209-16.
55. Couratier P, Sindou P, Esclaire F, Louvel E, Hugon J. Neuroprotective effects of riluzole in ALS CSF toxicity. Neuroreport. 1994 Apr 14;5(8):1012-4.
56. Gibson SB, Bromberg MB. Amyotrophic lateral sclerosis: drug therapy from the bench to the bedside. Semin Neurol. 2012 Jul;32(3):173-8.
57. Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve. 2002 Oct;26(4):438-58.
58. Van Damme P, Van Den Bosch L, Van Houtte E, Callewaert G, Robberecht W. GluR2-dependent properties of AMPA receptors determine the selective vulnerability of motor neurons to excitotoxicity. J Neurophysiol. 2002 Sep;88(3):1279-87.
59. Fray AE, Ince PG, Banner SJ, Milton ID, Usher PA, Cookson MR, et al. The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci. 1998 Aug;10(8):2481-9.
60. Maragakis NJ, Dykes-Hoberg M, Rothstein JD. Altered expression of the glutamate transporter EAAT2b in neurological disease. Ann Neurol. 2004 Apr;55(4):469-77.
61. 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.
62. Sasaki S, Komori T, Iwata M. Excitatory amino acid transporter 1 and 2 immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol. 2000 Aug;100(2):138-44.
63. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005 Jan 6;433(7021):73-7.
64. Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol. 1994 Dec;145(6):1271-9.
65. Liu J, Lillo C, Jonsson PA, Vande Velde C, Ward CM, Miller TM, et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron. 2004 Jul 8;43(1):5-17.
66. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, et al. 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):1105-16.
67. Afifi AK, Aleu FP, Goodgold J, MacKay B. Ultrastructure of atrophic muscle in amyotrophic lateral sclerosis. Neurology. 1966 May;16(5):475-81.
68. Hirano A, Donnenfeld H, Sasaki S, Nakano I. Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1984 Sep;43(5):461-70.
69. Hirano A, Nakano I, Kurland LT, Mulder DW, Holley PW, Saccomanno G. Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1984 Sep;43(5):471-80.
70. Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998 May 1;18(9):3241-50.
71. Higgins CM, Jung C, Xu Z. ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 2003 Jul 15;4:16.
72. Beal MF, Hyman BT, Koroshetz W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci. 1993 Apr;16(4):125-31.
73. Damiano M, Starkov AA, Petri S, Kipiani K, Kiaei M, Mattiazzi M, et al. Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J Neurochem. 2006 Mar;96(5):1349-61.
74. Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6465-7.
75. Browne SE, Bowling AC, Baik MJ, Gurney M, Brown RH, Jr., Beal MF. Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J Neurochem. 1998 Jul;71(1):281-7.
76. Groeneveld GJ, Veldink JH, van der Tweel I, Kalmijn S, Beijer C, de Visser M, et al. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann Neurol. 2003 Apr;53(4):437-45.
77. Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med. 1999 Mar;5(3):347-50.
78. Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M, et al. A clinical trial of creatine in ALS. Neurology. 2004 Nov 9;63(9):1656-61.
79. Manfredi G, Xu Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion. 2005 Apr;5(2):77-87.
80. Hollenbeck PJ, Saxton WM. The axonal transport of mitochondria. J Cell Sci. 2005 Dec 1;118(23):5411-9.
81. Perlson E, Maday S, Fu MM, Moughamian AJ, Holzbaur EL. Retrograde axonal transport: pathways to cell death? Trends Neurosci. 2010 Jul;33(7):335-44.
82. Chevalier-Larsen E, Holzbaur ELF. Axonal transport and neurodegenerative disease. Bba-Mol Basis Dis. 2006 Nov-Dec;1762(11-12):1094-108.
83. Hirano A. Cytopathology of amyotrophic lateral sclerosis. Adv Neurol. 1991;56:91-101.
84. Murakami T, Nagano I, Hayashi T, Manabe Y, Shoji M, Setoguchi Y, et al. Impaired retrograde axonal transport of adenovirus-mediated E. coli LacZ gene in the mice carrying mutant SOD1 gene. Neurosci Lett. 2001 Aug 10;308(3):149-52.
85. 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):50-6.
86. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006 Jun 2;312(5778):1389-92.
87. Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 2011 Mar;10(3):253-63.
88. Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012 Jul 26;487(7408):443-8.
89. Philips T, Bento-Abreu A, Nonneman A, Haeck W, Staats K, Geelen V, et al. Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain. 2013 Jan 31.
90. Gong YH, Parsadanian AS, Andreeva A, Snider WD, Elliott JL. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J Neurosci. 2000 Jan 15;20(2):660-5.
91. Lino MM, Schneider C, Caroni P. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neurosci. 2002 Jun 15;22(12):4825-32.
92. Pramatarova A, Laganiere 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):3369-74.
93. Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16021-6.
94. Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science. 2003 Oct 3;302(5642):113-7.
95. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008 Mar;11(3):251-3.
96. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007 Nov;10(11):1387-94.
97. Henkel JS, Beers DR, Zhao W, Appel SH. Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol. 2009 Dec;4(4):389-98.
98. Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol. 2009 May 29;210(1-2):3-12.
99. Almer G, Guegan C, Teismann P, Naini A, Rosoklija G, Hays AP, et al. Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann Neurol. 2001 Feb;49(2):176-85.
100. 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):1282-9.
101. Hall ED, Oostveen JA, Gurney ME. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia. 1998 Jul;23(3):249-56.
102. Engelhardt JI, Tajti J, Appel SH. Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol. 1993 Jan;50(1):30-6.
103. Drachman DB, Frank K, Dykes-Hoberg M, Teismann P, Almer G, Przedborski S, et al. Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann Neurol. 2002 Dec;52(6):771-8.
104. Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2002 Aug;10(3):268-78.
105. Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport. 2002 Jun 12;13(8):1067-70.
106. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500.
107. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010 Jan;119(1):7-35.
108. Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, 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):1604-9.
109. Levine JB, Kong J, Nadler M, Xu Z. Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia. 1999 Dec;28(3):215-24.
110. Gowing G, Philips T, Van Wijmeersch B, Audet JN, Dewil M, Van Den Bosch L, et al. Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci. 2008 Oct 8;28(41):10234-44.
111. Lepore AC, Dejea C, Carmen J, Rauck B, Kerr DA, Sofroniew MV, et al. Selective ablation of proliferating astrocytes does not affect disease outcome in either acute or chronic models of motor neuron degeneration. Exp Neurol. 2008 Jun;211(2):423-32.
112. Nagy D, Kato T, Kushner PD. Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J Neurosci Res. 1994 Jun 15;38(3):336-47.
113. Schiffer D, Cordera S, Cavalla P, Migheli A. Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis. J Neurol Sci. 1996 Aug;139 Suppl:27-33.
114. Sasaki S, Warita H, Abe K, Iwata M. Inducible nitric oxide synthase (iNOS) and nitrotyrosine immunoreactivity in the spinal cords of transgenic mice with a G93A mutant SOD1 gene. J Neuropathol Exp Neurol. 2001 Sep;60(9):839-46.
115. Turner BJ, Ackerley S, Davies KE, Talbot K. Dismutase-competent SOD1 mutant accumulation in myelinating Schwann cells is not detrimental to normal or transgenic ALS model mice. Hum Mol Genet. 2010 Mar 1;19(5):815-24.
116. Lobsiger CS, Boillee S, McAlonis-Downes M, Khan AM, Feltri ML, Yamanaka K, et al. Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4465-70.
117. Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci. 2013 May;16(5):571-9.
118. Nave KA. Myelination and support of axonal integrity by glia. Nature. 2010 Nov 11;468(7321):244-52.
119. Jahn O, Tenzer S, Werner HB. Myelin proteomics: molecular anatomy of an insulating sheath. Mol Neurobiol. 2009 Aug;40(1):55-72.
120. Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci. 2003 Mar;6(3):309-15.
121. Meletis K, Barnabe-Heider F, Carlen M, Evergren E, Tomilin N, Shupliakov O, et al. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol. 2008 Jul 22;6(7):e182.
122. Jurynczyk M, Selmaj K. Notch: a new player in MS mechanisms. J Neuroimmunol. 2010 Jan 25;218(1-2):3-11.
123. Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem. 2005 Jul;94(1):1-14.
124. Koehler-Stec EM, Simpson IA, Vannucci SJ, Landschulz KT, Landschulz WH. Monocarboxylate transporter expression in mouse brain. Am J Physiol. 1998 Sep;275(3 Pt 1):E516-24.
125. Pierre K, Pellerin L, Debernardi R, Riederer BM, Magistretti PJ. Cell-specific localization of monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain revealed by double immunohistochemical labeling and confocal microscopy. Neuroscience. 2000;100(3):617-27.
126. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999 Oct 15;343 Pt 2:281-99.
127. Rinholm JE, Hamilton NB, Kessaris N, Richardson WD, Bergersen LH, Attwell D. Regulation of oligodendrocyte development and myelination by glucose and lactate. J Neurosci. 2011 Jan 12;31(2):538-48.
128. Benarroch EE. Oligodendrocytes: Susceptibility to injury and involvement in neurologic disease. Neurology. 2009 May 19;72(20):1779-85.
129. Keirstead HS, Blakemore WF. Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J Neuropathol Exp Neurol. 1997 Nov;56(11):1191-201.
130. Redwine JM, Armstrong RC. In vivo proliferation of oligodendrocyte progenitors expressing PDGFalphaR during early remyelination. J Neurobiol. 1998 Nov 15;37(3):413-28.
131. Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci. 2008 Dec;11(12):1392-401.
132. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008 Feb 22;132(4):645-60.
133. Levine JM, Reynolds R, Fawcett JW. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 2001 Jan;24(1):39-47.
134. Keirstead HS, Levine JM, Blakemore WF. Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia. 1998 Feb;22(2):161-70.
135. Bergles DE, Roberts JD, Somogyi P, Jahr CE. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature. 2000 May 11;405(6783):187-91.
136. Butt AM, Duncan A, Hornby MF, Kirvell SL, Hunter A, Levine JM, et al. Cells expressing the NG2 antigen contact nodes of Ranvier in adult CNS white matter. Glia. 1999 Mar;26(1):84-91.
137. Trotter J, Karram K, Nishiyama A. NG2 cells: Properties, progeny and origin. Brain Res Rev. 2010 May;63(1-2):72-82.
138. Pfeiffer SE, Warrington AE, Bansal R. The oligodendrocyte and its many cellular processes. Trends Cell Biol. 1993 Jun;3(6):191-7.
139. Kondo T, Raff M. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science. 2000 Sep 8;289(5485):1754-7.
140. Raff MC, Miller RH, Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature. 1983 Jun 2-8;303(5916):390-6.
141. Zhang SC. Defining glial cells during CNS development. Nat Rev Neurosci. 2001 Nov;2(11):840-3.
142. Niebroj-Dobosz I, Rafalowska J, Fidzianska A, Gadamski R, Grieb P. Myelin composition of spinal cord in a model of amyotrophic lateral sclerosis (ALS) in SOD1G93A transgenic rats. Folia Neuropathol. 2007;45(4):236-41.
143. Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 2001 Apr;81(2):871-927.
144. Sanchez-Abarca LI, Tabernero A, Medina JM. Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia. 2001 Dec;36(3):321-9.
145. Walz W, Mukerji S. Lactate production and release in cultured astrocytes. Neurosci Lett. 1988 Apr 12;86(3):296-300.
146. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012 May 24;485(7399):517-21.
147. Li H, Richardson WD. Genetics meets epigenetics: HDACs and Wnt signaling in myelin development and regeneration. Nat Neurosci. 2009 Jul;12(7):815-7.
148. Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron. 1998 Jul;21(1):63-75.
149. Shawber C, Nofziger D, Hsieh JJ, Lindsell C, Bogler O, Hayward D, et al. Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway. Development. 1996 Dec;122(12):3765-73.
150. Kwon SM, Alev C, Lee SH, Asahara T. The molecular basis of Notch signaling: a brief overview. Adv Exp Med Biol. 2012;727:1-14.
151. Lathia JD, Mattson MP, Cheng A. Notch: from neural development to neurological disorders. J Neurochem. 2008 Dec;107(6):1471-81.
152. Louvi A, Artavanis-Tsakonas S. Notch and disease: a growing field. Semin Cell Dev Biol. 2012 Jun;23(4):473-80.
153. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89.
154. Le Borgne R, Bardin A, Schweisguth F. The roles of receptor and ligand endocytosis in regulating Notch signaling. Development. 2005 Apr;132(8):1751-62.
155. Talora C, Campese AF, Bellavia D, Felli MP, Vacca A, Gulino A, et al. Notch signaling and diseases: an evolutionary journey from a simple beginning to complex outcomes. Biochim Biophys Acta. 2008 Sep;1782(9):489-97.
156. Ables JL, Breunig JJ, Eisch AJ, Rakic P. Not(ch) just development: Notch signalling in the adult brain. Nat Rev Neurosci. 2011 May;12(5):269-83.
157. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999 Apr 30;284(5415):770-6.
158. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000 Feb;5(2):207-16.
159. Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565-97.
160. Petcherski AG, Kimble J. Mastermind is a putative activator for Notch. Curr Biol. 2000 Jun 29;10(13):R471-3.
161. Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci. 2009 May;66(10):1631-46.
162. Kovall RA. More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene. 2008 Sep 1;27(38):5099-109.
163. Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995 Sep 28;377(6547):355-8.
164. Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol. 2001 Nov;21(21):7403-15.
165. Takahashi T, Nowakowski RS, Caviness VS, Jr. Early ontogeny of the secondary proliferative population of the embryonic murine cerebral wall. J Neurosci. 1995 Sep;15(9):6058-68.
166. Li HS, Wang D, Shen Q, Schonemann MD, Gorski JA, Jones KR, et al. Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis. Neuron. 2003 Dec 18;40(6):1105-18.
167. Zhong W, Jiang MM, Weinmaster G, Jan LY, Jan YN. Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. Development. 1997 May;124(10):1887-97.
168. Kageyama R, Ohtsuka T, Kobayashi T. Roles of Hes genes in neural development. Dev Growth Differ. 2008 Jun;50 Suppl 1:S97-103.
169. Presente A, Andres A, Nye JS. Requirement of Notch in adulthood for neurological function and longevity. Neuroreport. 2001 Oct 29;12(15):3321-5.
170. Berezovska O, Xia MQ, Hyman BT. Notch is expressed in adult brain, is coexpressed with presenilin-1, and is altered in Alzheimer disease. J Neuropathol Exp Neurol. 1998 Aug;57(8):738-45.
171. Ehm O, Goritz C, Covic M, Schaffner I, Schwarz TJ, Karaca E, et al. RBPJkappa-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. J Neurosci. 2010 Oct 13;30(41):13794-807.
172. Imayoshi I, Sakamoto M, Yamaguchi M, Mori K, Kageyama R. Essential roles of Notch signaling in maintenance of neural stem cells in developing and adult brains. J Neurosci. 2010 Mar 3;30(9):3489-98.
173. Antonini A, Stryker MP. Rapid remodeling of axonal arbors in the visual cortex. Science. 1993 Jun 18;260(5115):1819-21.
174. Carlisle HJ, Kennedy MB. Spine architecture and synaptic plasticity. Trends Neurosci. 2005 Apr;28(4):182-7.
175. Wong RO, Ghosh A. Activity-dependent regulation of dendritic growth and patterning. Nat Rev Neurosci. 2002 Oct;3(10):803-12.
176. Berezovska O, McLean P, Knowles R, Frosh M, Lu FM, Lux SE, et al. Notch1 inhibits neurite outgrowth in postmitotic primary neurons. Neuroscience. 1999;93(2):433-9.
177. Sestan N, Artavanis-Tsakonas S, Rakic P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science. 1999 Oct 22;286(5440):741-6.
178. Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, et al. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9458-62.
179. De Strooper B, Konig G. Alzheimer's disease. A firm base for drug development. Nature. 1999 Dec 2;402(6761):471-2.
180. Park HC, Appel B. Delta-Notch signaling regulates oligodendrocyte specification. Development. 2003 Aug;130(16):3747-55.
181. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004 Aug 5;430(7000):631-9.
182. Ray WJ, Yao M, Nowotny P, Mumm J, Zhang W, Wu JY, et al. Evidence for a physical interaction between presenilin and Notch. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3263-8.
183. Hassan BA, Bermingham NA, He Y, Sun Y, Jan YN, Zoghbi HY, et al. atonal regulates neurite arborization but does not act as a proneural gene in the Drosophila brain. Neuron. 2000 Mar;25(3):549-61.
184. Arumugam TV, Chan SL, Jo DG, Yilmaz G, Tang SC, Cheng A, et al. Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke. Nat Med. 2006 Jun;12(6):621-3.
185. Woo HN, Park JS, Gwon AR, Arumugam TV, Jo DG. Alzheimer's disease and Notch signaling. Biochem Biophys Res Commun. 2009 Dec 25;390(4):1093-7.
186. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, et al. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch Neurol. 2008 Aug;65(8):1031-8.
187. Charil A, Filippi M. Inflammatory demyelination and neurodegeneration in early multiple sclerosis. J Neurol Sci. 2007 Aug 15;259(1-2):7-15.
188. John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med. 2002 Oct;8(10):1115-21.
189. Jurynczyk M, Jurewicz A, Bielecki B, Raine CS, Selmaj K. Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis. J Neuroimmunol. 2005 Dec 30;170(1-2):3-10.
190. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001 Dec;25(4):402-8.
191. Kolly C, Suter MM, Muller EJ. Proliferation, cell cycle exit, and onset of terminal differentiation in cultured keratinocytes: pre-programmed pathways in control of C-Myc and Notch1 prevail over extracellular calcium signals. J Invest Dermatol. 2005 May;124(5):1014-25.
192. Vogl MR, Reiprich S, Kuspert M, Kosian T, Schrewe H, Nave KA, et al. Sox10 Cooperates with the Mediator Subunit 12 during Terminal Differentiation of Myelinating Glia. J Neurosci. 2013 Apr 10;33(15):6679-90.
193. Dadon-Nachum M, Melamed E, Offen D. The "dying-back" phenomenon of motor neurons in ALS. J Mol Neurosci. 2011 Mar;43(3):470-7.
194. Woodhoo A, Alonso MB, Droggiti A, Turmaine M, D'Antonio M, Parkinson DB, et al. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci. 2009 Jul;12(7):839-47.
