Nucleocytoplasmic Transport Defects: Cause or Consequence in Neurodegeneration and Aging?

Yıl 2020, Cilt: 2 Sayı: 3, 143 - 153, 23.12.2020

İrem Armağan Emel Ulupınar

Öz

Nucleus is the most important organelle of a cell playing a critical role in the regulation of gene expression. The nuclear pore complexes (NPCs) spanning the NE are the largest protein complexes, having more than 30 different proteins called as nucleoporins (Nups). These structures play a key role in controlling bidirectional transport of RNA and specific proteins which carry nuclear import or export signals. Especially in long-lived cells, like neurons, protection of the nucleocytoplasmic transport machinery from accumulating external and internal insults has a special importance for maintaining genomic integrity and DNA repairement mechanisms. Recent studies suggest that structural and functional alterations in the NE and components of the NPC might lead to nucleocytoplasmic transport defects in both physiological aging and neurodegenerative disorders, in particular characterized by toxic protein aggregates. However, whether impaired nucleocytoplasmic transport is a cause or a consequence of such conditions is still unclear. In this review, it was aimed to summarize the molecular mechanisms underlying the nucleocytoplasmic transport defects. This information will not only provide insights to shared pathways in physiological and pathological conditions, but also open the way of thinking to develop novel therapeutic and/or protective approaches in the future.

Anahtar Kelimeler

Nucleocytoplasmic transport; Nuclear pore complex; Neurodegeneration;Aging.

Nucleocytoplasmic Transport Defects: Cause or Consequence in Neurodegeneration and Aging?

Öz

Çekirdek, hücrenin gen ekspresyonunun düzenlenmesinde kritik rol oynayan çok önemli bir organeldir. Nükleer zar içerisinde gömülü bulunan nükleer por kompleksleri (NPK) hücredeki en büyük protein kompleksleridir ve nükleoporin (Nups) olarak adlandırılan 30'dan fazla farklı proteine sahiptir. Bu yapılar, RNA'nın ve nükleer import veya export sinyalleri taşıyan spesifik proteinlerin çift yönlü olarak taşınımının kontrolünde önemli rol oynarlar. Özellikle de nöronlar gibi uzun ömürlü hücrelerde, genomik bütünlüğünün korunması ve DNA onarım mekanizmalarının işlevlerinin yerine getirebilmesi için nükleositoplazmik transport işletiminin giderek biriken iç ve dış hasarlardan korunması özel bir öneme sahiptir. Son çalışmalar, nükleer zardaki ve NPK bileşenlerindeki değişikliklerin hem fizyolojik yaşlanma hem de toksik protein agregatları ile karakterize olan nörodejeneratif hastalıklarda nükleositoplazmik transport bozukluklarına yol açabileceğine işaret etmektedir. Bununla birlikte, bozulmuş nükleositoplazmik taşınımın bu problemlerin nedeni mi yoksa sonucu mu olduğu konusu hala belirsizliğini korumaktadır.
Bu derlemede, nükleositoplazmik transport kusurlarının altında yatan moleküler mekanizmaların özetlenmesi amaçlanmıştır. Bu bilgiler, fizyolojik ve patolojik durumlarda gözlenen ortak mekanizmalara ilişkin öngörü sağlamakla kalmayıp, aynı zamanda gelecekte yeni tedavi edici ve/veya koruyucu yaklaşımlar geliştirilmesi için düşünce yolunu da açacaktır.

Anahtar Kelimeler

Nükleositoplazmik transport, Nükleer por kompleksi, Nörodejenerasyon, Yaşlanma

Kaynakça

• 1. Anna Tamburrino MD. Aged and Diseased Neurons Get Lost in Transport. CellPress.
• 2. Swift J, Discher DE. The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue. J Cell Sci. 2014;127(Pt 14):3005-15.
• 3. Martins F, Sousa J, Pereira CD, da Cruz ESOAB, Rebelo S. Nuclear envelope dysfunction and its contribution to the aging process. Aging Cell. 2020;19(5):e13143.
• 4. Strambio-De-Castillia C, Niepel M, Rout MP. The nuclear pore complex: bridging nuclear transport and gene regulation. Nat Rev Mol Cell Biol. 2010;11(7):490-501.
• 5. Gerace L, Blobel G. The nuclear envelope lamina is reversibly depolymerized during mitosis. Cell. 1980;19(1):277-87.
• 6. Hoelz A DE, Blobel G. G. The structure of the nuclear pore complex. Annu Rev Biochem. 2011.
• 7. Hoelz A, Debler EW, Blobel G. The structure of the nuclear pore complex. Annu Rev Biochem. 2011;80:613-43.
• 8. Sakuma S, D'Angelo MA. The roles of the nuclear pore complex in cellular dysfunction, aging and disease. Semin Cell Dev Biol. 2017;68:72-84.
• 9. Kim HJ, Taylor JP. Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases. Neuron. 2017;96(2):285-97.
• 10. D'Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009;136(2):284-95.
• 11. Toyama BH, Savas JN, Park SK, Harris MS, Ingolia NT, Yates JR, 3rd, et al. Identification of long-lived proteins reveals exceptional stability of essential cellular structures. Cell. 2013;154(5):971-82.
• 12. D'Angelo MA, Hetzer MW. The role of the nuclear envelope in cellular organization. Cell Mol Life Sci. 2006;63(3):316-32.
• 13. Fichtman B, Harel A. Stress and aging at the nuclear gateway. Mech Ageing Dev. 2014;135:24-32.
• 14. Wimmer C, Doye V, Grandi P, Nehrbass U, Hurt EC. A new subclass of nucleoporins that functionally interact with nuclear pore protein NSP1. The EMBO journal. 1992;11(13):5051-61.
• 15. Gallardo P, Salas-Pino S, Daga RR. A new role for the nuclear basket network. Microb Cell. 2017;4(12):423-5.
• 16. Mohr D, Frey S, Fischer T, Güttler T, Görlich D. Characterisation of the passive permeability barrier of nuclear pore complexes. The EMBO journal. 2009;28(17):2541-53.
• 17. Paine PL, Feldherr CM. Nucleocytoplasmic exchange of macromolecules. Exp Cell Res. 1972;74(1):81-98.
• 18. Fu X, Liang C, Li F, Wang L, Wu X, Lu A, et al. The Rules and Functions of Nucleocytoplasmic Shuttling Proteins. Int J Mol Sci. 2018;19(5).
• 19. Pemberton LF, Paschal BM. Mechanisms of receptor-mediated nuclear import and nuclear export. Traffic. 2005;6(3):187-98.
• 20. Moore MS. Nuclear pores: David and Goliath in nuclear transport. Curr Biol. 1995;5(12):1339-41.
• 21. Wen W, Meinkoth JL, Tsien RY, Taylor SS. Identification of a signal for rapid export of proteins from the nucleus. Cell. 1995;82(3):463-73.
• 22. Bischoff FR, Ponstingl H. Catalysis of guanine nucleotide exchange of Ran by RCC1 and stimulation of hydrolysis of Ran-bound GTP by Ran-GAP1. Methods Enzymol. 1995;257:135-44.
• 23. Bitetto G, Di Fonzo A. Nucleo-cytoplasmic transport defects and protein aggregates in neurodegeneration. Transl Neurodegener. 2020;9(1):25.
• 24. Gasiorowski JZ, Dean DA. Mechanisms of nuclear transport and interventions. Adv Drug Deliv Rev. 2003;55(6):703-16.
• 25. Ossareh-Nazari B, Bachelerie F, Dargemont C. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science. 1997;278(5335):141-4.
• 26. Dong X, Biswas A, Chook YM. Structural basis for assembly and disassembly of the CRM1 nuclear export complex. Nat Struct Mol Biol. 2009;16(5):558-60.
• 27. Kutay U, Lipowsky G, Izaurralde E, Bischoff FR, Schwarzmaier P, Hartmann E, et al. Identification of a tRNA-specific nuclear export receptor. Mol Cell. 1998;1(3):359-69.
• 28. Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. Rna. 2004;10(2):185-91.
• 29. Okamura M, Inose H, Masuda S. RNA Export through the NPC in Eukaryotes. Genes (Basel). 2015;6(1):124-49.
• 30. Wickramasinghe VO, Laskey RA. Control of mammalian gene expression by selective mRNA export. Nat Rev Mol Cell Biol. 2015;16(7):431-42.
• 31. Lari A, Arul Nambi Rajan A, Sandhu R, Reiter T, Montpetit R, Young BP, et al. A nuclear role for the DEAD-box protein Dbp5 in tRNA export. Elife. 2019;8.
• 32. Akey CW, Goldfarb DS. Protein import through the nuclear pore complex is a multistep process. J Cell Biol. 1989;109(3):971-82.
• 33. Paul S.AGUTTER DP. Nucleocytoplasmic transport. BiochemJ. 1994.
• 34. Robijns J, Houthaeve G, Braeckmans K, De Vos WH. Loss of Nuclear Envelope Integrity in Aging and Disease. Int Rev Cell Mol Biol. 2018;336:205-22.
• 35. D'Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009;136(2):284-95.
• 36. Benvegnù S. Nucleus-cytoplasm cross-talk in the aging brain. J Neurosci Res. 2020;98(2):247-61.
• 37. Wang X, Michaelis E. Selective neuronal vulnerability to oxidative stress in the brain. Frontiers in Aging Neuroscience. 2010;2(12).
• 38. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78(2):547-81.
• 39. Chandrasekaran A, Idelchik M, Melendez JA. Redox control of senescence and age-related disease. Redox Biol. 2017;11:91-102.
• 40. Savas JN, Toyama BH, Xu T, Yates JR, 3rd, Hetzer MW. Extremely long-lived nuclear pore proteins in the rat brain. Science (New York, NY). 2012;335(6071):942-.
• 41. Brown CR, Kennedy CJ, Delmar VA, Forbes DJ, Silver PA. Global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexes. Genes Dev. 2008;22(5):627-39.
• 42. Fifková E, Tonks M, Cullen-Dockstader K. Changes in the nuclear pore complexes of the dentate granule cells in aged rats. Exp Neurol. 1987;95(3):755-62.
• 43. Mertens J, Paquola ACM, Ku M, Hatch E, Böhnke L, Ladjevardi S, et al. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell. 2015;17(6):705-18.
• 44. Mackenzie IR, Neumann M. Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies. J Neurochem. 2016;138 Suppl 1:54-70.
• 45. Jovicic A, Paul JW, 3rd, Gitler AD. Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia. J Neurochem. 2016;138 Suppl 1:134-44.
• 46. Solomon DA, Stepto A, Au WH, Adachi Y, Diaper DC, Hall R, et al. A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration. Brain. 2018;141(10):2908-24.
• 47. Lester E, Parker R. The Tau of Nuclear-Cytoplasmic Transport. Neuron. 2018;99(5):869-71.
• 48. Tripathi T, Kalita J. Abnormal Microtubule Dynamics Impair the Nuclear-Cytoplasmic Transport in Dementia. ACS Chem Neurosci. 2019;10(3):1133-4.
• 49. Sheffield LG, Miskiewicz HB, Tannenbaum LB, Mirra SS. Nuclear pore complex proteins in Alzheimer disease. J Neuropathol Exp Neurol. 2006;65(1):45-54.
• 50. Mastroeni D, Chouliaras L, Grover A, Liang WS, Hauns K, Rogers J, et al. Reduced RAN expression and disrupted transport between cytoplasm and nucleus; a key event in Alzheimer's disease pathophysiology. PLoS One. 2013;8(1):e53349.
• 51. Truant R, Atwal RS, Burtnik A. Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease. Prog Neurobiol. 2007;83(4):211-27.
• 52. Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, et al. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science. 2016;351(6269):173-6.