ROLE OF MOTOR PROTEINS IN NEURODEGENERATIVE DISEASES

Yıl 2024, , 263 - 274, 01.09.2024

Fatma Nur Zobar , Zekiye Tuba Tüylü Küçükkılınç

https://doi.org/10.52794/hujpharm.1509048

Öz

Neurodegenerative diseases are associated with various risk factors such as heredity, age, and lifestyle. Numerous studies have proven that motor proteins and disruptions in axonal transport play significant roles in the pathway leading to neurodegenerative diseases. Motor proteins are dynamic structures that move toward the (+) and (-) ends of microtubules in neuronal cells to promote axonal transport and intracellular communication. Axonal transport abnormalities are linked to the existence of protein aggregates, which lead to neurodegeneration in a variety of neurodegenerative illnesses, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Motor proteins, including as kinesins and dyneins, are in charge of axonal transport, which is an energy-dependent mechanism that transports cargoes like proteins, organelles, RNA, and synaptic vesicles between the cell body and axon terminals. Axonal transport is an important mechanism for neurons, which have a relatively large volume and are required to maintain intracellular homeostasis. Impaired axonal transport, abnormalities in the genes encoding axonal transport elements, or problems with energy production or use can impede intracellular communication, disrupt intercellular communication, and cause neuronal death. Irreversible and progressive neuronal losses can cause neurodegeneration, which leads to the onset of neurodegenerative disorders.

Anahtar Kelimeler

Neurodegenerative diseases, motor proteins, axonal transport, kinesin, dynein

MOTOR PROTEİNLERİN NÖRODEJENERATİF HASTALIKLARDAKİ ROLÜ

Öz

Nörodejeneratif hastalıkların görülme sıklığı günümüzde artmaya ve birçok insanı etkilemeye devam etmektedir. Nörodejeneratif hastalılar kalıtım, yaş, yaşam tarzı gibi farklı risk faktörleri ile ilişkilendirilmektedir. Yapılan birçok çalışma ile motor proteinler ve aksonal taşınmadaki bozuklukların, nörodejenerasyona ve nörodejeneratif hastalıklara sebep olan yolakta önemli rolleri olduğu kanıtlanmıştır. Motor proteinler, nöronal hücrelerde mikrotübülün (+) ve (-) uçlarına yürüyerek hücre içi iletimi ve aksonal taşınmayı sağlayan dinamik yapılardır. Yapılan incelemelerde, nörodejeneratif hastalığa sahip insan ve hayvan beyinlerinde, motor protein mekanizmasında bozuklukların olduğuna rastlanmıştır. Alzheimer, Parkinson, Amyotrofik Lateral Sklerozis ve Huntington Hastalığı gibi farklı nörodejeneratif hastalıklarda; nörodejenerasyona sebep olan protein agregatların varlığı aksonal taşınmadaki bozukluklar ile ilişkilendirilmektedir. Motor proteinler olan kinesin ve dineinler; protein, organel, RNA, sinaptik veziküller gibi kargoların hücre gövdesi ve akson uçları arasında taşınmasını sağlayan ve enerji gerektiren aksonal taşınmadan sorumlu elemanlardır. Hacimce oldukça büyük olan nöronlar için aksonal taşınma kritik bir olaydır ve hücre içi homoestazisinin devam ettirilebilmesi için zorunludur. Taşınma anında aksaklık gelişmesi, aksonal taşınma elemanlarını kodlayan genlerde mutasyonların meydana gelmesi, enerji üretimi veya kullanımında sorun meydana gelmesi gibi durumlar hücre içi iletimin engellenmesine, hücreler arası iletişimin bozulmasına ve nöronal apoptoza sebep olabilmektedir. Geri dönüşü olmayan ve ilerleyici nöron kayıpları ise nörodejenerasyonla sonuçlanarak nörodejeneratif hastalıkların ortaya çıkmasına neden olabilmektedir.

Anahtar Kelimeler

Nörodejeneratif hastalıklar, aksonal taşınma, motor protein, kinesin, dinein

Kaynakça

• 1. Thakur S, Dhapola R, Sarma P, Medhi B, Reddy DH. Neuroinflammation in Alzheimer’s Disease: Current Progress in Molecular Signaling and Therapeutics. Inflammation. 2023;46(1):1-17. https://doi.org/10.1007/s10753-022-01721-1
• 2. Przedborski S, Vila M, Jackson-Lewis V. Neurodegeneration: what is it and where are we? J Clin Invest. 2003;111(1):3-10. https://doi.org/10.1172/JCI17522
• 3. Jellinger KA. Basic mechanisms of neurodegeneration: a critical update. J Cell Mol Med. 2010;14(3):457-87. https://doi. org/10.1111/j.1582-4934.2010.01010.x
• 4. Demir G, Özen S, Çetin H, Darcan Ş, Gökşen D. Effect of education on impaired hypoglycemia awareness and glycemic variability in children and adolescents with type 1 diabetes mellitus. J.Clin Res Pediatr Endocrinol. 2019;11(2):189. https://doi.org/10.4274/jcrpe.galenos.2019.2019.0009
• 5. Brady ST, Morfini GA. Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases. Neurobiol Dis. 2017;105:273-82. https://doi.org/10.1016/j. nbd.2017.04.010
• 6. Cason SE, Holzbaur ELF. Selective motor activation in organelle transport along axons. Nat Rev Mol Cell Biol. 2022;23(11):699-714. https://doi.org/10.1038/s41580-022- 00491-w
• 7. Cavalli V, Kujala P, Klumperman J, Goldstein LSB. Sunday Driver links axonal transport to damage signaling. J Cell Biol. 2005;168(5):775-87. https://doi.org/10.1083/jcb.200410136
• 8. Goldstein L. Axonal and Dendritic Transport by Dyneins and Kinesins in Neurons. Encyclopedia of Neuroscience. 2009:1101-8. https://doi.org/10.1016/B978-008045046- 9.00708-7
• 9. Maryann E. Martone MHE. Neuron. Encyclopedia of the Human Brain. 2002;3:507-23. https://doi.org/10.1016/B0-12- 227210-2/00245-4.
• 10. Black MM. Axonal transport: The orderly motion of axonal structures. Methods Cell Biol. 2016;131:1-19. https://doi. org/10.1016/bs.mcb.2015.06.001
• 11. Maday S, Twelvetrees AE, Moughamian AJ, Holzbaur EL. Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron. 2014;84(2):292-309. https://doi. org/10.1016/j.neuron.2014.10.019
• 12. Millecamps S, Julien JP. Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci. 2013;14(3):161-76. https://doi.org/10.1038/nrn3380
• 13. Coleman M. Molecular signaling: How do axons die? Adv Genet. 2011;73:185-217. https://doi.org/10.1016/B978-0-12- 380860-8.00005-7.
• 14. Perlson E, Maday S, Fu MM, Moughamian AJ, Holzbaur EL. Retrograde axonal transport: pathways to cell death? Trends Neurosci. 2010;33(7):335-44. https://doi.org/10.1016/j. tins.2010.03.006
• 15. Sleigh JN, Rossor AM, Fellows AD, Tosolini AP, Schiavo G. Axonal transport and neurological disease. Nat Rev Neurol. 2019;15(12):691-703. https://doi.org/10.1038/s41582-019- 0257-2
• 16. Jellinger KA. Basic mechanisms of neurodegeneration: a critical update. J Cell Mol Med. 2010;14(3):457-87. https://doi. org/10.1111/j.1582-4934.2010.01010.x
• 17. Duke T. Push or pull? Teams of motor proteins have it both ways. Proceedings of the National Academy of Sciences. 2002;99(10):6521-3. https://doi.org/10.1073/pnas.112200199
• 18. Hirokawa N, Noda Y, Tanaka Y, Niwa S. Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol. 2009;10(10):682-96. https://doi.org/10.1038/nrm2774
• 19. Hirokawa N, Tanaka Y. Kinesin superfamily proteins (KIFs): Various functions and their relevance for important phenomena in life and diseases. Exp Cell Res. 2015;334(1):16-25. https://doi.org/10.1016/j.yexcr.2015.02.016
• 20. Siddiqui N, Straube A. Intracellular Cargo Transport by Kinesin- 3 Motors. Biochemistry (Mosc). 2017;82(7):803-15. https://doi.org/10.1134/S0006297917070057
• 21. Hirokawa N, Noda Y. Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol Rev. 2008;88(3):1089-118. https://doi.org/10.1152/ physrev.00023.2007
• 22. Wang W, Cao L, Wang C, Gigant B, Knossow M. Kinesin, 30 years later: Recent insights from structural studies. Protein Sci. 2015;24(7):1047-56. https://doi.org/10.1002/pro.2697
• 23. Gerdes JM, Katsanis N. Microtubule transport defects in neurological and ciliary disease. Cell Mol Life Sci. 2005;62(14):1556-70. https://doi.org/10.1007/s00018-005- 5007-5
• 24. Hirokawa N, Niwa S, Tanaka Y. Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron. 2010;68(4):610-38. https://doi. org/10.1016/j.neuron.2010.09.039
• 25. Lu W, Gelfand VI. Moonlighting Motors: Kinesin, Dynein, and Cell Polarity. Trends Cell Biol. 2017;27(7):505-14. https://doi.org/10.1016/j.tcb.2017.02.005
• 26. Olenick MA, Holzbaur EL. Dynein activators and adaptors at a glance. J Cell Sci. 2019;132(6):jcs227132. https://doi. org/10.1242/jcs.227132
• 27. Chowdhury S, Ketcham SA, Schroer TA, Lander GC. Structural organization of the dynein-dynactin complex bound to microtubules. Nat Struct Mol Biol. 2015;22(4):345-7. https:// doi.org/10.1038/nsmb.2996
• 28. Chevalier-Larsen E, Holzbaur EL. Axonal transport and neurodegenerative disease. Biochim Biophys Acta. 2006;1762(11- 12):1094-108. https://doi.org/10.1016/j.bbadis.2006.04.002
• 29. Soo KY, Farg M, Atkin JD. Molecular motor proteins and amyotrophic lateral sclerosis. Int J Mol Sci. 2011;12(12):9057-82. https://doi.org/10.3390/ijms12129057
• 30. Odronitz F, Kollmar M. Drawing the tree of eukaryotic life based on the analysis of 2,269 manually annotated myosins from 328 species. Genome Biol. 2007;8(9):R196. https://doi. org/10.1186/gb-2007-8-9-r196
• 31. Cooper. GM. Microtubule Motors and Movements, 2000. Erişim adresi: https://www.ncbi.nlm.nih.gov/books/NBK9833/
• 32. De Vos KJ, Grierson AJ, Ackerley S, Miller CC. Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci. 2008;31:151-73. https://doi.org/10.1146/annurev.neuro. 31.061307.090711
• 33. Olanow CW, McNaught K. Parkinson’s disease, proteins, and prions: Milestones. Movement Disorders. 2011;26(6):1056- 71. https://doi.org/10.1002/mds.23767
• 34. Stokin GB, Goldstein LS. Axonal transport and Alzheimer’s disease. Annu Rev Biochem. 2006;75:607-27. https://doi. org/10.1146/annurev.biochem.75.103004.142637
• 35. Brown A. Axonal Transport. In: Pfaff DW, Volkow ND, editors. Neuroscience in the 21st Century: From Basic to Clinical. New York, NY: Springer New York; 2016. p. 333-79. https:// doi.org/10.1007/978-1-4939-3474-4
• 36. Apostolova LG. Alzheimer Disease. Continuum (Minneap Minn). 2016;22(2 Dementia):419-34. https://doi.org/10.1212/ CON.0000000000000307
• 37. Tüylü Küçükkilinç ZT, Odabaşı MD. Alzheimer Hastalığı Tedavisindeki Güncel Yaklaşımlar. Hacettepe University Journal of the Faculty of Pharmacy. 2021;41(4):266-80. https://doi. org/10.52794/hujpharm.955421
• 38. Stokin GB, Goldstein LSB. Axonal Transport and Alzheimer’s Disease. Annual Review of Biochemistry. 2006;75(Volume 75, 2006):607-27. https://doi.org/10.1146/annurev.biochem. 75.103004.142637
• 39. García-Morales V, González-Acedo A, Melguizo-Rodríguez L, Pardo-Moreno T, Costela-Ruiz VJ, Montiel-Troya M, Ramos-Rodríguez JJ. Current understanding of the physiopathology, diagnosis and therapeutic approach to Alzheimer’s disease. Biomedicines. 2021 Dec 14;9(12):1910. https://doi. org/10.3390/biomedicines9121910
• 40. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. The Lancet Neurology. 2013;12(4):357- 67. https://doi.org/10.1016/S1474-4422(13)70044-9
• 41. Gunawardena S, Goldstein LSB. Cargo-carrying motor vehicles on the neuronal highway: Transport pathways and neurodegenerative disease. Journal of Neurobiology. 2004;58(2):258- 71. https://doi.org/10.1002/neu.10319
• 42. Roy S, Zhang B, Lee VM, Trojanowski JQ. Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol. 2005;109(1):5-13. https://doi.org/10.1007/ s00401-004-0952-x
• 43. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3(1):17013. https://doi.org/10.1038/nrdp.2017.13
• 44. Saha AR, Hill J, Utton MA, Asuni AA, Ackerley S, Grierson AJ, et al. Parkinson’s disease α-synuclein mutations exhibit defective axonal transport in cultured neurons. Journal of J Cell Sci. 2004;117(7):1017-24. https://doi.org/10.1242/jcs.00967
• 45. Tunçel F, Atasever Arslan B. Axonal Transport of Alpha Synuclein fibrils in Parkinsons Disease. The J Neuro Behav Sci. 2018:1. https://doi.org/10.5455/JNBS.1530369473
• 46. Dauer W, Przedborski S. Parkinson’s Disease: Mechanisms and Models. Neuron. 2003;39(6):889-909. https://doi. org/10.1016/s0896-6273(03)00568-3
• 47. Chung CY, Koprich JB, Siddiqi H, Isacson O. Dynamic Changes in Presynaptic and Axonal Transport Proteins Combined with Striatal Neuroinflammation Precede Dopaminergic Neuronal Loss in a Rat Model of AAV α-Synucleinopathy. J Neurosci. 2009;29(11):3365-73. https://doi.org/10.1523/JNEUROSCI. 5427-08.2009
• 48. Rui Q, Ni H, Li D, Gao R, Chen G. The Role of LRRK2 in Neurodegeneration of Parkinson Disease. Curr Neuropharmacol. 2018;16(9):1348-57. https://doi.org/10.2174/157015 9X16666180222165418
• 49. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10(1):83- 98. https://doi.org/10.1016/S1474-4422(10)70245-3
• 50. Walker FO. Huntington’s disease. The Lancet. 2007;369(9557):218-28. https://doi.org/10.1016/S0140- 6736(07)60111-1
• 51. Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington’s Disease pathology. Curr Trends Neurol. 2011;5:65-78. https://doi.org/10.1016/j. neuron.2016.02.003
• 52. Li S-H, Li X-J. Huntington and its Role in Neuronal Degeneration. The Neuroscientist. 2004;10(5):467-75. https://doi. org/10.1177/1073858404266777
• 53. Brady ST, Morfini GA. Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases. Neurobiol Dis. 2017;105:273-82. https://doi.org/10.1016/j. nbd.2017.04.010
• 54. Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangone H, Cordelières FP, et al. Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport along Microtubules. Cell. 2004;118(1):127- 38. https://doi.org/10.1016/j.cell.2004.06.018
• 55. Engelender S, Sharp AH, Colomer V, Tokito MK, Lanahan A, Worley P, et al. Huntingtin-associated Protein 1 (HAP1) Interacts with the p150Glued Bubunit of Dynactin. Hum Mol Genet. 1997;6(13):2205-12. https://doi.org/10.1093/ hmg/6.13.2205
• 56. Taran AS, Shuvalova LD, Lagarkova MA, Alieva IB. Huntington’s Disease-An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components. Cells. 2020;9(6). https://doi.org/10.3390/cells9061514
• 57. Li SH, Lam S, Cheng AL, Li XJ. Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Hum Mol Genet. 2000;9(19):2859-67. https://doi.org/10.1093/ hmg/9.19.2859
• 58. Neusch C, Bähr M, Schneider-Gold C. Glia cells in amyotrophic lateral sclerosis: New clues to understanding an old disease? Muscle & Nerve. 2007;35(6):712-24. https://doi. org/10.1002/mus.20768
• 59. Corona JC, Tovar-y-Romo LB, Tapia R. Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis. Expert Opin Ther Targets. 2007;11(11):1415-28. https://doi.or g/10.1517/14728222.11.11.1415
• 60. Brenner D, Yilmaz R, Müller K, Grehl T, Petri S, Meyer T, et al. Hot-spot KIF5A mutations cause familial ALS. Brain. 2018;141(3):688-97. https://doi.org/10.1093/brain/awx370
• 61. Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron. 2018;97(6):1268-83. e6. https://doi. org/10.1016/j.neuron.2018.02.027
• 62. Williamson TL, Bruijn LI, Zhu Q, Anderson KL, Anderson SD, Julien J-P, et al. Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant. Proceedings of the National Academy of Sciences. 1998;95(16):9631-6. https://doi. org/10.1073/pnas.95.16.9631
• 63. Morfini GA, Burns M, Binder LI, Kanaan NM, LaPointe N, Bosco DA, et al. Axonal transport defects in neurodegenerative diseases. J Neurosci. 2009;29(41):12776-86. https://doi. org/10.1523/JNEUROSCI.3463-09.2009
• 64. De Vos KJ, Chapman AL, Tennant ME, Manser C, Tudor EL, Lau KF, et al. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet. 2007;16(22):2720-8. https://doi.org/10.1093/hmg/ddm226
• 65. 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. https:// doi.org/10.1212/01.wnl.0000134608.83927.b1
• 66. Puls I, Jonnakuty C, LaMonte BH, Holzbaur ELF, Tokito M, Mann E, et al. Mutant dynactin in motor neuron disease. Nat Genet. 2003;33(4):455-6. https://doi.org/10.1038/ng1123
• 67. Perlson E, Jeong GB, Ross JL, Dixit R, Wallace KE, Kalb RG, et al. A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. J Neurosci. 2009;29(31):9903- 17. https://doi.org/10.1523/JNEUROSCI.0813-09.2009
• 68. Guo W, Stoklund Dittlau K, Van Den Bosch L. Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications. Semin Cell Dev Biol. 2020;99:133- 50. https://doi.org/10.1016/j.semcdb.2019.07.010