Öz
İlk olarak on dokuzuncu yüzyılda Charcot tarafından tanımlanan Amyotrofik Lateral Skleroz (ALS), genellikle üç ile beş yıllık bir sağkalım ile seyreden, sürekli ilerleyici bir nörodejeneratif hastalıktır. Motor nöronlarda dejenerasyon ve ölüm ile karakterize olup, kortikal motor hücreler(piramidal ve Betz hücreleri), kortikospinal trakt, ve ön boynuz hücrelerinde belirgin aksonal kayıp görülür. ALS’nin etiyolojisi tam olarak bilinmemekle birlikte, patogenezinde pek çok farklı etmenin rol oynadığı ileri sürülmektedir. Genetik, oksidatif stres, glutamat eksitoksisitesi, mitokondrial disfonksiyon, aksonal transport bozukluğu, nöroinflamasyon, RNA bozuklukları bunlardan başlıcalarıdır. Yine nörotrofik faktörler, organeller arası trafiğin bozulması, sinyal yolaklarında bozukluk, metabolik değişiklikler gibi faktörlerin de süreçte rol oynadığı düşünülmektedir. Bu derlemede ALS hastalığının patogenezi gözden geçirilmiştir.
Anahtar Kelimeler
amyotrophic lateral sclerosis pathogenesis etiology genetic mitochondrial dysfunction
Kaynakça
- 1. Byrne S, Walsh C, Lynch C, Bede P, Elamin M, Kenna K, et al. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(6):623–7.
- 2. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62.
- 3. 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;13(1):43–7.
- 4. Gurney ME. Transgenic animal models of familial amyotrophic lateral sclerosis. J Neurol. 1997;244 Suppl 2:S15-20.
- 5. Boillee S, Cleveland DW. Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1. J Clin Invest. 2008;118(2):474–8.
- 6. Durham HD, Roy J, Dong L, Figlewicz DA. Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol. 1997;56(5):523–30.
- 7. Zou Z-Y, Zhou Z-R, Che C-H, Liu C-Y, He R-L, Huang H-P. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88(7):540–9.
- 8. 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;72(2):245–56.
- 9. Haeusler AR, Donnelly CJ, Periz G, Simko EAJ, Shaw PG, Kim M-S, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014;507(7491):195–200.
- 10. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56–61.
- 11. Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. 2014;345(6201):1139–45.
- 12. Waite AJ, Baumer D, East S, Neal J, Morris HR, Ansorge O, et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging. 2014;35(7):1779.e5-1779.e13.
- 13. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668–72.
- 14. Kwiatkowski TJJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8.
- 15. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, et al. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009;11(3):497–508.
- 16. 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;28(1):18–25.
- 17. Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S. Glutamate receptors: RNA editing and death of motor neurons. Nature. 2004;427(6977):801.
- 18. Tadic V, Prell T, Lautenschlaeger J, Grosskreutz J. The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis. Front Cell Neurosci [Internet]. 2014;30(8):147.
- 19. 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;43(1):5–17.
- 20. Kepp KP. Genotype-property patient-phenotype relations suggest that proteome exhaustion can cause amyotrophic lateral sclerosis. PLoS One. 2015;10(3):e0118649.
- 21. Mizusawa H, Matsumoto S, Yen SH, Hirano A, Rojas-Corona RR, Donnenfeld H. Focal accumulation of phosphorylated neurofilaments within anterior horn cell in familial amyotrophic lateral sclerosis. Acta Neuropathol. 1989;79(1):37–43.
- 22. Sterneck E, Kaplan DR, Johnson PF. Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells. J Neurochem. 1996;67(4):1365–74.
- 23. Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld AD, Kurt A, et al. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology. 2004;63(4):724–6.
- 24. Geloso MC, Corvino V, Marchese E, Serrano A, Michetti F, D’Ambrosi N. The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches. Front Aging Neurosci [Internet]. 2017;25(9):242.
- 25. Ito D, Suzuki N. Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology. 2011;77(17):1636–43.
- 26. Zhou Q, Lehmer C, Michaelsen M, Mori K, Alterauge D, Baumjohann D, et al. Antibodies inhibit transmission and aggregation of C9orf72 poly‐ GA dipeptide repeat proteins . EMBO Mol Med. 2017;9(5):687–702.
Öz
Amyotrophic Lateral Sclerosis (ALS), first described by Charcot in the nineteenth century, is a progressive neurodegenerative disease, usually with a three to five-year survival. ALS is characterized by degeneration and death in motor neurons. Cortical motor cells (pyramidal and Betz cells), corticospinal tract and anterior horn cells show prominent axonal loss. Although the etiology of ALS is not known exactly, it is suggested that many different factors play a role in its pathogenesis. Genetics, oxidative stress, glutamate excitotoxicity, mitochondrial dysfunction, axonal transport disorder, neuroinflammation, RNA disorders are the main ones. Factors such as neurotrophic factors, impaired intercellular traffic, disturbance of signaling pathways and metabolic changes are thought to play a role in the process. In this article, pathogenesis of ALS disease is reviewed.
Anahtar Kelimeler
amyotrophic lateral sclerosis pathogenesis etiology genetic mitochondrial dysfunction
Kaynakça
- 1. Byrne S, Walsh C, Lynch C, Bede P, Elamin M, Kenna K, et al. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(6):623–7.
- 2. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62.
- 3. 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;13(1):43–7.
- 4. Gurney ME. Transgenic animal models of familial amyotrophic lateral sclerosis. J Neurol. 1997;244 Suppl 2:S15-20.
- 5. Boillee S, Cleveland DW. Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1. J Clin Invest. 2008;118(2):474–8.
- 6. Durham HD, Roy J, Dong L, Figlewicz DA. Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol. 1997;56(5):523–30.
- 7. Zou Z-Y, Zhou Z-R, Che C-H, Liu C-Y, He R-L, Huang H-P. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88(7):540–9.
- 8. 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;72(2):245–56.
- 9. Haeusler AR, Donnelly CJ, Periz G, Simko EAJ, Shaw PG, Kim M-S, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014;507(7491):195–200.
- 10. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56–61.
- 11. Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. 2014;345(6201):1139–45.
- 12. Waite AJ, Baumer D, East S, Neal J, Morris HR, Ansorge O, et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging. 2014;35(7):1779.e5-1779.e13.
- 13. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668–72.
- 14. Kwiatkowski TJJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8.
- 15. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, et al. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009;11(3):497–508.
- 16. 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;28(1):18–25.
- 17. Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S. Glutamate receptors: RNA editing and death of motor neurons. Nature. 2004;427(6977):801.
- 18. Tadic V, Prell T, Lautenschlaeger J, Grosskreutz J. The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis. Front Cell Neurosci [Internet]. 2014;30(8):147.
- 19. 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;43(1):5–17.
- 20. Kepp KP. Genotype-property patient-phenotype relations suggest that proteome exhaustion can cause amyotrophic lateral sclerosis. PLoS One. 2015;10(3):e0118649.
- 21. Mizusawa H, Matsumoto S, Yen SH, Hirano A, Rojas-Corona RR, Donnenfeld H. Focal accumulation of phosphorylated neurofilaments within anterior horn cell in familial amyotrophic lateral sclerosis. Acta Neuropathol. 1989;79(1):37–43.
- 22. Sterneck E, Kaplan DR, Johnson PF. Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells. J Neurochem. 1996;67(4):1365–74.
- 23. Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld AD, Kurt A, et al. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology. 2004;63(4):724–6.
- 24. Geloso MC, Corvino V, Marchese E, Serrano A, Michetti F, D’Ambrosi N. The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches. Front Aging Neurosci [Internet]. 2017;25(9):242.
- 25. Ito D, Suzuki N. Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology. 2011;77(17):1636–43.
- 26. Zhou Q, Lehmer C, Michaelsen M, Mori K, Alterauge D, Baumjohann D, et al. Antibodies inhibit transmission and aggregation of C9orf72 poly‐ GA dipeptide repeat proteins . EMBO Mol Med. 2017;9(5):687–702.
Ayrıntılar
| Birincil Dil | Türkçe |
|---|---|
| Konular | Nöroloji ve Nöromüsküler Hastalıklar |
| Bölüm | Derleme |
| Yazarlar | |
| Yayımlanma Tarihi | 14 Mayıs 2020 |
| Gönderilme Tarihi | 6 Kasım 2019 |
| Kabul Tarihi | 19 Mart 2020 |
| Yayımlandığı Sayı | Yıl 2020 Cilt: 13 Sayı: 2 |
Kaynak Göster
Cited By
Anatomical and Radiological Evaluation of Brainstem Morphometry of Subjects with Amyotrophic Lateral Sclerosis
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Amyotrofik Lateral Skleroz Patofizyolojisi ve Tedavi Yaklaşımları
Hacettepe University Journal of the Faculty of Pharmacy
https://doi.org/10.52794/hujpharm.1064372
