ALS PATOFİZYOLOJİSİ: NEYİ, NE KADAR BİLİYORUZ?

Yıl 2008, Cilt: 21 Sayı: 1, 102 - 111, 24.06.2015

Kayıhan Uluç Barış İşak Tülin Tanrıdağ Önder Us

Öz

Amyotrofik lateral skleroz (ALS) esas olarak serebral korteks, beyin sapı ve spinal korddaki motor nöronları
etkileyen progresif seyirli nörodejeneratif bir hastalıktır. Çoğu vakanın sporadik olduğu ALS’de familyal
geçiş %5-10’dur ve bunların yaklaşık olarak %10-20’sinde neden süperoksid dismutaz-1 enziminde meydana
gelen mutasyondur. Familyal ve sporadik vakaların klinik ve patolojik bulguları birbirlerine büyük
benzerlikler göstermektedir. Bu özgün derleme yazısında ALS’nin patofizyolojisinde etkili olduğu öne
sürülen mekanizmalar varsayımsal tümleyici bir model ile tartışılacaktır.

Anahtar Kelimeler

ALS, Patofizyoloji, Varsayımsal tümleyici model

Kaynakça

• 1. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. J Neurol Sci 1994;124 Suppl:96-107.
• 2. Goetz CG. Amyotrophic lateral sclerosis: early contributions of Jean-Martin Charcot. Muscle Nerve 2000;23:336-343.
• 3. Nelson LM. Epidemiology of ALS. Clin Neurosci 1995;3:327-331.
• 4. Beghi E, Logroscino G, Chio A, et al. The epidemiology of ALS and the role of populationbased registries. Biochim Biophys Acta 2006;1762(11-12):1150-1157.
• 5. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: A population-based study. Arch Neurol 2000;57:1171-1176.
• 6. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362(6415):59-62.
• 7. Manfredi G, Xu Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion 2005;5:77-87.
• 8. Vandenberghe N. [Where is the role of the genetic investigations in ALS?]. Rev Neurol (Paris) 2006;162 Spec No 2:4S96-94S101.
• 9. Beckman JS, Estevez AG, Crow JP, Barbeito L. Superoxide dismutase and the death of motoneurons in ALS. Trends Neurosci 2001;24(11 Suppl):S15-20.
• 10. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet 1998;19:171-174.
• 11. Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve 2002;26:438-458.
• 12. Rothstein JD, Bristol LA, Hosler B, Brown RH, Jr., Kuncl RW. Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. Proc Natl Acad Sci U S A 1994;91:4155-4159.
• 13. Greenlund LJ, Deckwerth TL, Johnson EM, Jr. Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neuron 1995;14:303-315.
• 14. Reaume AG, Elliott JL, Hoffman EK, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 1996;13:43-47.
• 15. Estevez AG, Sampson JB, Zhuang YX, et al. Liposome-delivered superoxide dismutase prevents nitric oxide-dependent motor neuron death induced by trophic factor withdrawal. Free Radic Biol Med 2000;28:437-446.
• 16. Beckman JS, Carson M, Smith CD, Koppenol WH. ALS, SOD and peroxynitrite. Nature 1993;364(6438):584.
• 17. Crow JP, Ye YZ, Strong M, Kirk M, Barnes S, Beckman JS. Superoxide dismutase catalyzes nitration of tyrosines by peroxynitrite in the rod and head domains of neurofilament-L. J Neurochem 1997;69:1945-1953.
• 18. Bogdanov MB, Ramos LE, Xu Z, Beal MF. Elevated "hydroxyl radical" generation in vivo in an animal model of amyotrophic lateral sclerosis. J Neurochem 1998;71:1321-1324.
• 19. Tiwari A, Hayward LJ. Familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase are susceptible to disulfide reduction. J Biol Chem 2003;278:5984-5992.
• 20. Hayward LJ, Rodriguez JA, Kim JW, et al. Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem 2002;277:15923-15931.
• 21. Bruijn LI, Houseweart MK, Kato S, et al. Aggregation and motor neuron toxicity of an ALSlinked SOD1 mutant independent from wild-type SOD1. Science 1998;281:1851-1854.
• 22. Gredal O, Moller SE. Effect of branched-chain amino acids on glutamate metabolism in amyotrophic lateral sclerosis. J Neurol Sci 1995;129:40-43.
• 23. Plaitakis A, Caroscio JT. Abnormal glutamate metabolism in amyotrophic lateral sclerosis. Ann Neurol 1987;22:575-579.
• 24. Plaitakis A, Constantakakis E, Smith J. The neuroexcitotoxic amino acids glutamate and aspartate are altered in the spinal cord and brain in amyotrophic lateral sclerosis. Ann Neurol 1988;24: 446-449.
• 25. Fray AE, Ince PG, Banner SJ, et al. The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci 1998;10:2481-2489.
• 26. 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;38:73-84.
• 27. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994;330:585-591.
• 28. 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;347(9013):1425-1431.
• 29. Louvel E, Hugon J, Doble A. Therapeutic advances in amyotrophic lateral sclerosis. Trends Pharmacol Sci 1997;18:196-203.
• 30. Ludolph AC, Meyer T, Riepe MW. The role of excitotoxicity in ALS--what is the evidence? J Neurol 2000;247 Suppl 1:I7-16.
• 31. Shaw PJ, Ince PG. Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J Neurol 1997;244 Suppl 2:S3-14.
• 32. Stout AK, Raphael HM, Kanterewicz BI, Klann E, Reynolds IJ. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1998;1:366-373.
• 33. Shaw PJ, Ince PG, Matthews JN, Johnson M, Candy JM. N-methyl-D-aspartate (NMDA) receptors in the spinal cord and motor cortex in motor neuron disease: a quantitative autoradiographic study using [3H]MK- 801. Brain Res 1994;637:297-302. 109 Marmara Medical Journal
• 34. Shaw PJ, Eggett CJ. Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 2000;247 Suppl 1:I17-27.
• 35. Askmark H, Aquilonius SM, Gillberg PG, Liedholm LJ, Stalberg E, Wuopio R. A pilot trial of dextromethorphan in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1993;56:197-200.
• 36. Blin O, Azulay JP, Desnuelle C, Bille-Turc F, Braguer D, Besse D, et al. A controlled one-year trial of dextromethorphan in amyotrophic lateral sclerosis. Clin Neuropharmacol 1996;19:189-192.
• 37. Weiss JH, Sensi SL. Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration. Trends Neurosci 2000;23:365- 371.
• 38. Carriedo SG, Yin HZ, Weiss JH. Motor neurons are selectively vulnerable to AMPA/kainate receptormediated injury in vitro. J Neurosci 1996;16:4069- 4079.
• 39. Ikonomidou C, Qin Qin Y, Labruyere J, Olney JW. Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 1996;55:211-224.
• 40. Mennini T, Cagnotto A, Carvelli L, et al. Biochemical and pharmacological evidence of a functional role of AMPA receptors in motor neuron dysfunction in mnd mice. Eur J Neurosci 1999;11:1705-1710.
• 41. Canton T, Bohme GA, Boireau A, et al. RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis. J Pharmacol Exp Ther 2001;299:314-322.
• 42. Van Damme P, Leyssen M, Callewaert G, Robberecht W, Van Den Bosch L. The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Lett 2003;343:81-84.
• 43. Rao SD, Weiss JH. Excitotoxic and oxidative crosstalk between motor neurons and glia in ALS pathogenesis. Trends Neurosci 2004;27:17-23.
• 44. Vandenberghe W, Robberecht W, Brorson JR. AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability. J Neurosci 2000;20:123-132.
• 45. 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;88:1279-1287.
• 46. von Lewinski F, Keller BU. Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS. Trends Neurosci 2005;28:494-500.
• 47. Alexianu ME, Ho BK, Mohamed AH, La Bella V, Smith RG, Appel SH. The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis. Ann Neurol 1994;36:846-858.
• 48. Ince P, Stout N, Shaw P, et al. Parvalbumin and calbindin D-28k in the human motor system and in motor neuron disease. Neuropathol Appl Neurobiol 1993;19:291-299.
• 49. Banner SJ, Fray AE, Ince PG, Steward M, Cookson MR, Shaw PJ. The expression of the glutamate reuptake transporter excitatory amino acid transporter 1 (EAAT1) in the normal human CNS and in motor neurone disease: an immunohistochemical study. Neuroscience 2002;109:27-44.
• 50. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 1999;81:163-221.
• 51. Dong LP, Wang TY. Effects of puerarin against glutamate excitotoxicity on cultured mouse cerebral cortical neurons. Zhongguo Yao Li Xue Bao 1998;19:339-342.
• 52. Atsumi T. The ultrastructure of intramuscular nerves in amyotrophic lateral sclerosis. Acta Neuropathol (Berl) 1981;55:193-198.
• 53. Hirano A, Donnenfeld H, Sasaki S, Nakano I. Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 1984;43:461-470.
• 54. Sasaki S, Iwata M. Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. Neurology 1996;47:535-540.
• 55. Siklos L, Engelhardt J, Harati Y, Smith RG, Joo F, Appel SH. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis. Ann Neurol 1996;39:203-216.
• 56. Wiedemann FR, Winkler K, Kuznetsov AV, et al. Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci 1998;156:65-72.
• 57. Vielhaber S, Kunz D, Winkler K, et al. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 2000;123 ( Pt 7):1339-1348.
• 58. 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;46:787-790.
• 59. Dal Canto MC, Gurney ME. Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res 1995;676:25-40.
• 60. 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;14:1105- 1116.
• 61. Sargsyan SA, Monk PN, Shaw PJ. Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis. Glia 2005;51:241-253.
• 62. 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;20:660-665.
• 63. Lino MM, Schneider C, Caroni P. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neurosci 2002;22:4825-4832.
• 64. Clement AM, Nguyen MD, Roberts EA, et al. Wildtype nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 2003;302(5642):113-117.