.: DERLEME
Mikrotübül Yapı, Organizasyon ve Hataları: Spinal Müsküler Atrofi ve Amyotrofik Lateral Skleroz
Microtubule Structure, Organization and Defects: Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis
Turkiye Klinikleri J Med Sci. 2019;39(2):221-30
doi: 10.5336/medsci.2018-63881
Makale Dili: TR
Tam Metin
ÖZET
Mikrotubuller, mikrofilamentler ve ara filamentler ile birlikte hucre iskeletini oluşturmaktadır. Alfa ve beta tubulin proteinlerinin biraraya gelmesiyle oluşan mikrotubuller, ici boş ve silindirik yapılar olup dinamik ozellik gostermekte, polimerizasyon ile uzamakta, depolimerizasyon ile kısalmaktadır. Mikrotubullerin yapısal duzenlenmesinde, farklı tubulin izotiplerinin yanı sıra tubulin post-translasyonel modifikasyonları (asetilasyon, detirozinasyon vb) ile mikrotubule bağlanan proteinler (MAP1B, TAU, statmin vb) rol oynamaktadır. Mikrotubuller hucre morfolojisinin belirlenmesi, hucre icinde organel, vezikul ve makromolekullerin (RNA, protein) taşınması, hucre bolunmesi, hucre farklılaşması ve hucre gocunde gorev almaktadır. Bu nedenle, mikrotubul iskeletinin doğru kurulması, korunması ve yapısının duzenlenmesi farklı hucresel fonksiyonların yerine getirilebilmesi icin gereklidir. Noronlar gibi uzun omurlu ve ozelleşmiş morfolojiye sahip hucrelerde ise mikrotubul stabilitesinin korunması yapı ve fonksiyon acısından onem taşımaktadır. Son yıllarda yapılan calışmalarda, mikrotubul iskelet hatalarının farklı norodejeneratif hastalıkların patomekanizmasında yer aldığı ve ortak olarak akzonal transportun bozulduğuna dair bulgular elde edilmiştir. Saptanan hataların, tubulin ya da mikrotubul ile ilişkili proteinleri kodlayan genlerdeki mutasyonların yanı sıra bu proteinlerdeki ifade veya post-translasyonel modifikasyon değişiklikleri nedeniyle ortaya cıkabileceği saptanmıştır. Bu derlemede, mikrotubullerin yapısı ve organizasyonunu duzenleyen temel mekanizmalar ozetlenmiş, ayrıca mikrotubul iskeleti hatalarının gorulduğu norodejeneratif hastalıklara ornek olarak Spinal muskuler atrofi'ler (proksimal SMA, SMALED1 ve SMALED2) ve Amyotrofik lateral skleroz'a (ALS) ait literaturde yer alan bulgular sunulmuştur.
Anahtar Kelimeler: Tübülin; mikrotübüller; SMA; ALS
Mikrotubuller, mikrofilamentler ve ara filamentler ile birlikte hucre iskeletini oluşturmaktadır. Alfa ve beta tubulin proteinlerinin biraraya gelmesiyle oluşan mikrotubuller, ici boş ve silindirik yapılar olup dinamik ozellik gostermekte, polimerizasyon ile uzamakta, depolimerizasyon ile kısalmaktadır. Mikrotubullerin yapısal duzenlenmesinde, farklı tubulin izotiplerinin yanı sıra tubulin post-translasyonel modifikasyonları (asetilasyon, detirozinasyon vb) ile mikrotubule bağlanan proteinler (MAP1B, TAU, statmin vb) rol oynamaktadır. Mikrotubuller hucre morfolojisinin belirlenmesi, hucre icinde organel, vezikul ve makromolekullerin (RNA, protein) taşınması, hucre bolunmesi, hucre farklılaşması ve hucre gocunde gorev almaktadır. Bu nedenle, mikrotubul iskeletinin doğru kurulması, korunması ve yapısının duzenlenmesi farklı hucresel fonksiyonların yerine getirilebilmesi icin gereklidir. Noronlar gibi uzun omurlu ve ozelleşmiş morfolojiye sahip hucrelerde ise mikrotubul stabilitesinin korunması yapı ve fonksiyon acısından onem taşımaktadır. Son yıllarda yapılan calışmalarda, mikrotubul iskelet hatalarının farklı norodejeneratif hastalıkların patomekanizmasında yer aldığı ve ortak olarak akzonal transportun bozulduğuna dair bulgular elde edilmiştir. Saptanan hataların, tubulin ya da mikrotubul ile ilişkili proteinleri kodlayan genlerdeki mutasyonların yanı sıra bu proteinlerdeki ifade veya post-translasyonel modifikasyon değişiklikleri nedeniyle ortaya cıkabileceği saptanmıştır. Bu derlemede, mikrotubullerin yapısı ve organizasyonunu duzenleyen temel mekanizmalar ozetlenmiş, ayrıca mikrotubul iskeleti hatalarının gorulduğu norodejeneratif hastalıklara ornek olarak Spinal muskuler atrofi'ler (proksimal SMA, SMALED1 ve SMALED2) ve Amyotrofik lateral skleroz'a (ALS) ait literaturde yer alan bulgular sunulmuştur.
Anahtar Kelimeler: Tübülin; mikrotübüller; SMA; ALS
ABSTRACT
Microtubules are one of the basic elements of the cytoskeleton together with microfilaments and intermediate filaments. Microtubules are hollow cylindrical structures, which are formed by alpha and beta-tubulin proteins. Microtubules are dynamic structures, which grow by polymerization and shrink by depolimerization. Structure of microtubules is regulated by different tubulin isotypes as well as post-translational modifications of tubulin (acetylation, detyrosination etc.) and microtubule-regulating proteins (MAP1B, TAU, stathmin, etc.). Microtubules plays role in cellular morphology, intracellular organelle, vesicle and macromolecules (RNA, protein) transport, cell division, cell differentiation and cell migration as well. Therefore, the correct establishment and maintanence of microtubule structure are necessary for the different cellular functions. Maintanence of microtubule stability is structurally and functionally important for long-lived cells having specialized morphology like neurons. Recent studies have shown that microtubule defects are involved in the pathomechanism of different neurodegenerative diseases. Impaired axonal transport has been proposed as a common mechanism for such diseases. Microtubule defects can occur due to mutations in genes encoding tubulin or associated proteins as well as changes in expression or post-translational modifications of these proteins. In this review, the basic mechanisms which regulate microtubule structure and organization are summarized together with its defects in neurodegenerative diseases; spinal muscular atrophies (proximal SMA, SMALED1 and SMALED2) and amyotrophic lateral sclerosis (ALS).
Keywords: Tubulin; microtubules; SMA; ALS
Microtubules are one of the basic elements of the cytoskeleton together with microfilaments and intermediate filaments. Microtubules are hollow cylindrical structures, which are formed by alpha and beta-tubulin proteins. Microtubules are dynamic structures, which grow by polymerization and shrink by depolimerization. Structure of microtubules is regulated by different tubulin isotypes as well as post-translational modifications of tubulin (acetylation, detyrosination etc.) and microtubule-regulating proteins (MAP1B, TAU, stathmin, etc.). Microtubules plays role in cellular morphology, intracellular organelle, vesicle and macromolecules (RNA, protein) transport, cell division, cell differentiation and cell migration as well. Therefore, the correct establishment and maintanence of microtubule structure are necessary for the different cellular functions. Maintanence of microtubule stability is structurally and functionally important for long-lived cells having specialized morphology like neurons. Recent studies have shown that microtubule defects are involved in the pathomechanism of different neurodegenerative diseases. Impaired axonal transport has been proposed as a common mechanism for such diseases. Microtubule defects can occur due to mutations in genes encoding tubulin or associated proteins as well as changes in expression or post-translational modifications of these proteins. In this review, the basic mechanisms which regulate microtubule structure and organization are summarized together with its defects in neurodegenerative diseases; spinal muscular atrophies (proximal SMA, SMALED1 and SMALED2) and amyotrophic lateral sclerosis (ALS).
Keywords: Tubulin; microtubules; SMA; ALS
REFERANSLAR:
- Conde C, Cáceres A. Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci. 2009;10(5):319-32. [Crossref] [PubMed]
- Muroyama A, Lechler T. Microtubule organization, dynamics and functions in differentiated cells. Development. 2017;144(17): 3012-21. [Crossref] [PubMed] [PMC]
- Wu J, Akhmanova A. Microtubule-organizing centers. Annu Rev Cell Dev Biol. 2017;33:51-75. [Crossref] [PubMed]
- Akhmanova A, Steinmetz MO. Control of microtubule organization and dynamics: two ends in the limelight. Nat Rev Mol Cell Biol. 2015;16(12):711-26. [Crossref] [PubMed]
- Chakraborti S, Natarajan K, Curiel J, Janke C, Liu J. The emerging role of the tubulin code: from the tubulin molecule to neuronal function and disease. Cytoskeleton (Hoboken). 2016;73(10):521-50. [Crossref] [PubMed]
- Janke C. The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol. 2014;206(4):461-72. [Crossref] [PubMed] [PMC]
- Gadadhar S, Bodakuntla S, Natarajan K, Janke C. The tubulin code at a glance. J Cell Sci. 2017;130(8):1347-53. [Crossref] [PubMed]
- Janke C, Bulinski JC. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol. 2011;12(12):773-86. [Crossref] [PubMed]
- Song Y, Brady ST. Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol. 2015;25(3):125-36. [Crossref] [PubMed] [PMC]
- Magiera MM, Singh P, Gadadhar S, Janke C. Tubulin posttranslational modifications and emerging links to human disease. Cell. 2018;173(6):1323-27. [Crossref] [PubMed]
- Xu Z, Schaedel L, Portran D, Aguilar A, Gaillard J, Marinkovich MP, et al. Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science. 2017; 356(6335):328-32. [Crossref] [PubMed] [PMC]
- Aillaud C, Bosc C, Peris L, Bosson A, Heemeryck P, Van Dijk J, et al. Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation. Science. 2017;358(6369):1448-53. [Crossref] [PubMed]
- Poulain FE, Sobel A. The microtubule network and neuronal morphogenesis: dynamic and coordinated orchestration through multiple players. Mol Cell Neurosci. 2010;43(1):15-32.[Crossref] [PubMed]
- Lyle K, Kumar P, Wittmann T. SnapShot: microtubule regulators I. Cell. 2009;136(2): 380.e1. [Crossref] [PubMed] [PMC]
- Tortosa E, Galjart N, Avila J, Sayas CL. MAP1B regulates microtubule dynamics by sequestering EB1/3 in the cytosol of developing neuronal cells. EMBO J. 2013;32(9):1293306. [Crossref] [PubMed] [PMC]
- Monroy BY, Sawyer DL, Ackermann BE, Borden MM, Tan TC, Ori-McKenney KM. Competition between microtubule-associated proteins directs motor transport. Nat Commun. 2018;9(1):1487. [Crossref] [PubMed] [PMC]
- Dubey J, Ratnakaran N, Koushika SP. Neurodegeneration and microtubule dynamics: death by a thousand cuts. Front Cell Neurosci. 2015;9:343. [Crossref] [PubMed] [PMC]
- Brunden KR, Lee VM, Smith AB 3rd, Trojanowski JQ, Ballatore C. Altered microtubule dynamics in neurodegenerative disease: therapeutic potential of microtubule-stabilizing drugs. Neurobiol Dis. 2017;105:328-35. [Crossref] [PubMed] [PMC]
- Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophydetermining gene. Cell. 1995;80(1):155-65. [Crossref]
- Pearn J. Classification of spinal muscular atrophies. Lancet. 1980;1(8174):919-22.[Crossref]
- Munsat TL, Davies KE. International SMA consortium meeting (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992;2(56):423-8. [Crossref]
- Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228-37.[Crossref]
- Bora-Tatar G, Erdem-Yurter H. Investigations of curcumin and resveratrol on neurite outgrowth: perspectives on spinal muscular atro phy. Biomed Res Int. 2014;2014:709108. [Crossref] [PubMed] [PMC]
- Bowerman M, Shafey D, Kothary R. Smn depletion alters profilin II expression and leads to upregulation of the RhoA/ROCK pathway and defects in neuronal integrity. J Mol Neurosci. 2007;32(2):120-31. [Crossref] [PubMed]
- Jablonka S, Karle K, Sandner B, Andreassi C, von Au K, Sendtner M. Distinct and overlapping alterations in motor and sensory neurons in a mouse model of spinal muscular atrophy. Hum Mol Genet. 2006;15(3):511-8. [Crossref] [PubMed]
- Rossoll W, Jablonka S, Andreassi C, Kröning AK, Karle K, Monani UR, et al. Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. J Cell Biol. 2003;163(4):801-12.[Crossref] [PubMed] [PMC]
- McWhorter ML, Monani UR, Burghes AH, Beattie CE. Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. J Cell Biol. 2003;162(5):919-31. [Crossref] [PubMed] [PMC]
- Torres-Benito L, Neher MF, Cano R, Ruiz R, Tabares L. SMN requirement for synaptic vesicle, active zone and microtubule postnatal organization in motor nerve terminals. PLoS One. 2011;6(10):e26164. [Crossref] [PubMed] [PMC]
- Wen HL, Lin YT, Ting CH, Lin-Chao S, Li H, Hsieh-Li HM. Stathmin, a microtubule-destabilizing protein, is dysregulated in spinal muscular atrophy. Hum Mol Genet. 2010;19(9): 1766-78. [Crossref] [PubMed]
- Wen HL, Ting CH, Liu HC, Li H, Lin-Chao S. Decreased stathmin expression ameliorates neuromuscular defects but fails to prolong survival in a mouse model of spinal muscular atrophy. Neurobiol Dis. 2013;52:94-103.[Crossref] [PubMed]
- Miller N, Feng Z, Edens BM, Yang B, Shi H, Sze CC, et al. Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy. J Neurosci. 2015;35(15): 6038-50. [Crossref] [PubMed] [PMC]
- Harms MB, Ori-McKenney KM, Scoto M, Tuck EP, Bell S, Ma D, et al. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology. 2012;78(22): 1714-20. [Crossref] [PubMed] [PMC]
- Martinez Carrera LA, Gabriel E, Donohoe CD, Hölker I, Mariappan A, Storbeck M, et al. Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development. Hum Mol Genet. 2018;27(10):1772-84. [Crossref] [PubMed]
- Sheng C, Pavani S, Xiaojie Z, Weidong L. Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener. 2013;8(28):2-15.[Crossref] [PubMed] [PMC]
- Clark JA, Yeaman EJ, Blizzard CA, Chuckowree JA, Dickson TC. A case for microtubule vulnerability in amyotrophic lateral sclerosis: altered dynamics during disease. Front Cell Neurosci. 2016;10:204. [Crossref] [PubMed] [PMC]
- Smith BN, Ticozzi N, Fallini C, Gkazi AS, Topp S, Kenna KP, et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron. 2014; 84(2):324-31. [Crossref] [PubMed] [PMC]
- Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012;488(7412):499-503.[Crossref] [PubMed] [PMC]
- Henty-Ridilla JL, Juanes MA, Goode BL. Profilin directly promotes microtubule growth through residues mutated in amyotrophic lateral sclerosis. Curr Biol. 2017;27(22):353543.e4. [Crossref] [PubMed] [PMC]
- Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, et al. Mutant dynactin in motor neuron disease. Nat Genet. 2003;33(4): 455-6. [Crossref] [PubMed]
- Münch 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. [Crossref] [PubMed]
- Fanara P, Banerjee J, Hueck RV, Harper MR, Awada M, Turner H, et al. Stabilization of hyperdynamic microtubules is neuroprotective in amyotrophic lateral sclerosis. J Biol Chem. 2007;282(32):23465-72. [Crossref] [PubMed]
- Nguyen MD, Larivière RC, Julien JP. Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron. 2001;30(1):135-47.[Crossref]
- Farah AC, Nguyen MD, Julien JP, Leclerc N. Altered levels and distribution of microtubuleassociated proteins before disease onset in a mouse model of amyotrophic lateral sclerosis. J Neurochem. 2003;84(1):77-86. [Crossref] [PubMed]
- Bellouze S, Baillat G, Buttigieg D, de la Grange P, Rabouille C, Haase G. Stathmin 1/2-triggered microtubule loss mediates Golgi fragmentation in mutant SOD1 motor neurons. Mol Neurodegener. 2016;11(1):43. [Crossref] [PubMed] [PMC]
- Gal J, Chen J, Barnett KR, Yang L, Brumley E, Zhu H. HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation. J Biol Chem. 2013;288(21): 15035-45. [Crossref] [PubMed] [PMC]
- Scotter EL, Chen HJ, Shaw CE. TDP-43 Proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics. 2015;12(2):352-63. [Crossref] [PubMed] [PMC]
- Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7(5):409-16. [Crossref]
- Coyne AN, Siddegowda BB, Estes PS, Johannesmeyer J, Kovalik T, Daniel SG, et al. Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a drosophila model of amyotrophic lateral sclerosis. J Neurosci. 2014;34(48):15962-74. [Crossref] [PubMed] [PMC]
- Letournel F, Bocquet A, Dubas F, Barthelaix A, Eyer J. Stable tubule only polypeptides (STOP) proteins co-aggregate with spheroid neurofilaments in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2003; 62(12): 1211-9. [Crossref] [PubMed]
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