Skip to main content
SpringerLink
Log in

RNA Nucleocytoplasmic Transport Defects in Neurodegenerative Diseases

  • Chapter
  • First Online:
Book cover RNA Metabolism in Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 20))

Abstract

In eukaryotic cells, transcription and translation are compartmentalized by the nuclear membrane, requiring an active transport of RNA from the nucleus into the cytoplasm. This is accomplished by a variety of transport complexes that contain either a member of the exportin family of proteins and translocation fueled by GTP hydrolysis or in the case of mRNA by complexes containing the export protein NXF1. Recent evidence indicates that RNA transport is altered in a number of different neurodegenerative diseases including Huntington’s disease, Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Alterations in RNA transport predominately fall into three categories: Alterations in the nuclear membrane and mislocalization and aggregation of the nucleoporins that make up the nuclear pore; alterations in the Ran gradient and the proteins that control it which impacts exportin based nuclear export; and alterations of proteins that are required for the export of mRNA leading nuclear accumulation of mRNA.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Paine PL. Nucleocytoplasmic movement of fluorescent tracers microinjected into living salivary gland cells. J Cell Biol. 1975;66(3):652–7.

    Article  CAS  PubMed  Google Scholar 

  2. De Robertis EM, Longthorne RF, Gurdon JB. Intracellular migration of nuclear proteins in Xenopus oocytes. Nature. 1978;272(5650):254–6.

    Article  PubMed  Google Scholar 

  3. Dingwall C, Sharnick SV, Laskey RA. A polypeptide domain that specifies migration of nucleoplasmin into the nucleus. Cell. 1982;30(2):449–58.

    Article  CAS  PubMed  Google Scholar 

  4. Segref A, et al. Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. EMBO J. 1997;16(11):3256–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Herold A, Klymenko T, Izaurralde E. NXF1/p15 heterodimers are essential for mRNA nuclear export in Drosophila. RNA. 2001;7(12):1768–80.

    PubMed  PubMed Central  CAS  Google Scholar 

  6. Thomas F, Kutay U. Biogenesis and nuclear export of ribosomal subunits in higher eukaryotes depend on the CRM1 export pathway. J Cell Sci. 2003;116(Pt 12):2409–19.

    Article  CAS  PubMed  Google Scholar 

  7. Wild T, et al. A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export. PLoS Biol. 2010;8(10):e1000522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rouquette J, Choesmel V, Gleizes PE. Nuclear export and cytoplasmic processing of precursors to the 40S ribosomal subunits in mammalian cells. EMBO J. 2005;24(16):2862–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fornerod M, et al. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90(6):1051–60.

    Article  CAS  PubMed  Google Scholar 

  10. Watanabe M, et al. Involvement of CRM1, a nuclear export receptor, in mRNA export in mammalian cells and fission yeast. Genes Cells. 1999;4(5):291–7.

    Article  CAS  PubMed  Google Scholar 

  11. Kutay U, et al. Identification of a tRNA-specific nuclear export receptor. Mol Cell. 1998;1(3):359–69.

    Article  CAS  PubMed  Google Scholar 

  12. Arts GJ, Fornerod M, Mattaj IW. Identification of a nuclear export receptor for tRNA. Curr Biol. 1998;8(6):305–14.

    Article  CAS  PubMed  Google Scholar 

  13. Lund E, et al. Nuclear export of microRNA precursors. Science. 2004;303(5654):95–8.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reichelt R, et al. Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components. J Cell Biol. 1990;110(4):883–94.

    Article  CAS  PubMed  Google Scholar 

  16. Cronshaw JM, et al. Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol. 2002;158(5):915–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Frey S, Gorlich D. A saturated FG-repeat hydrogel can reproduce the permeability properties of nuclear pore complexes. Cell. 2007;130(3):512–23.

    Article  CAS  PubMed  Google Scholar 

  18. Fukuda M, et al. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997;390(6657):308–11.

    Article  CAS  PubMed  Google Scholar 

  19. Bischoff FR, Ponstingl H. Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature. 1991;354(6348):80–2.

    Article  CAS  PubMed  Google Scholar 

  20. Brennan CM, Gallouzi IE, Steitz JA. Protein ligands to HuR modulate its interaction with target mRNAs in vivo. J Cell Biol. 2000;151(1):1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Topisirovic I, et al. Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP. EMBO J. 2009;28(8):1087–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang J, et al. Two closely related human nuclear export factors utilize entirely distinct export pathways. Mol Cell. 2001;8(2):397–406.

    Article  CAS  PubMed  Google Scholar 

  23. Henderson BR, Eleftheriou A. A comparison of the activity, sequence specificity, and CRM1-dependence of different nuclear export signals. Exp Cell Res. 2000;256(1):213–24.

    Article  CAS  PubMed  Google Scholar 

  24. Kalderon D, et al. A short amino acid sequence able to specify nuclear location. Cell. 1984;39(3 Pt 2):499–509.

    Article  CAS  PubMed  Google Scholar 

  25. Petosa C, et al. Architecture of CRM1/Exportin1 suggests how cooperativity is achieved during formation of a nuclear export complex. Mol Cell. 2004;16(5):761–75.

    Article  CAS  PubMed  Google Scholar 

  26. Yi R, et al. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003;17(24):3011–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Okada C, et al. A high-resolution structure of the pre-microRNA nuclear export machinery. Science. 2009;326(5957):1275–9.

    Article  CAS  PubMed  Google Scholar 

  28. Strasser K, et al. TREX is a conserved complex coupling transcription with messenger RNA export. Nature. 2002;417(6886):304–8.

    Article  CAS  PubMed  Google Scholar 

  29. McCloskey A, et al. hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science. 2012;335(6076):1643–6.

    Article  CAS  PubMed  Google Scholar 

  30. Reed R, Cheng H. TREX, SR proteins and export of mRNA. Curr Opin Cell Biol. 2005;17(3):269–73.

    Article  CAS  PubMed  Google Scholar 

  31. Cheng H, et al. Human mRNA export machinery recruited to the 5′ end of mRNA. Cell. 2006;127(7):1389–400.

    Article  CAS  PubMed  Google Scholar 

  32. Viphakone N, et al. TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nat Commun. 2012;3:1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wickramasinghe VO, Stewart M, Laskey RA. GANP enhances the efficiency of mRNA nuclear export in mammalian cells. Nucleus. 2010;1(5):393–6.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kohler A, et al. Yeast Ataxin-7 links histone deubiquitination with gene gating and mRNA export. Nat Cell Biol. 2008;10(6):707–15.

    Article  CAS  PubMed  Google Scholar 

  35. Sheffield LG, et al. Nuclear pore complex proteins in Alzheimer disease. J Neuropathol Exp Neurol. 2006;65(1):45–54.

    Article  CAS  PubMed  Google Scholar 

  36. Gasset-Rosa F, et al. Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron. 2017;94(1):48–57e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Grima JC, et al. Mutant Huntingtin disrupts the nuclear pore complex. Neuron. 2017;94(1):93–107e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shang J, et al. Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. Neuroscience. 2017;350:158–68.

    Article  CAS  PubMed  Google Scholar 

  39. Freibaum BD, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015;525(7567):129–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang K, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Boehringer A, et al. ALS associated mutations in matrin 3 alter protein-protein interactions and impede mRNA nuclear export. Sci Rep. 2017;7(1):14529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Suhr ST, et al. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J Cell Biol. 2001;153(2):283–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kinoshita Y, et al. Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2009;68(11):1184–92.

    Article  CAS  PubMed  Google Scholar 

  44. Boeynaems S, et al. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci Rep. 2016;6:20877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shi KY, et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc Natl Acad Sci U S A. 2017;114(7):E1111–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lee KH, et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell. 2016;167(3):774–788e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Woerner AC, et al. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science. 2016;351(6269):173–6.

    Article  CAS  Google Scholar 

  48. Ahmed Z, et al. Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol. 2010;177(1):311–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen-Plotkin AS, et al. Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. Hum Mol Genet. 2008;17(10):1349–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ward ME, et al. Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med. 2014;211(10):1937–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cho KI, et al. Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell Mol Life Sci. 2012;69(20):3511–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cho KI, et al. Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes. Dis Model Mech. 2017;10(5):559–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stalekar M, et al. Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport. Neuroscience. 2015;293:157–70.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang YJ, et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci. 2016;19(5):668–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hautbergue GM, et al. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat Commun. 2017;8:16063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kaneb HM, et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet. 2015;24(5):1363–73.

    Article  CAS  PubMed  Google Scholar 

  57. Kim JE, et al. Altered nucleocytoplasmic proteome and transcriptome distributions in an in vitro model of amyotrophic lateral sclerosis. PLoS One. 2017;12(4):e0176462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rossi S, et al. Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. J Cell Sci. 2015;128(9):1787–99.

    Article  CAS  PubMed  Google Scholar 

  59. Rabut G, Lenart P, Ellenberg J. Dynamics of nuclear pore complex organization through the cell cycle. Curr Opin Cell Biol. 2004;16(3):314–21.

    Article  CAS  PubMed  Google Scholar 

  60. D'Angelo MA, et al. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009;136(2):284–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Savas JN, et al. Extremely long-lived nuclear pore proteins in the rat brain. Science. 2012;335(6071):942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA

    Ashley Boehringer & Robert Bowser

  2. School of Life Sciences, Arizona State University, Phoenix, AZ, USA

    Ashley Boehringer

Authors
  1. Ashley Boehringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Bowser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Bowser .

Editor information

Editors and Affiliations

  1. Department of Neurobiology and Neurology, Dignityhealth St. Joseph’s Hospital, Barrow Neurological Institute, Phoenix, Arizona, USA

    Rita Sattler

  2. Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Christopher J. Donnelly

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Boehringer, A., Bowser, R. (2018). RNA Nucleocytoplasmic Transport Defects in Neurodegenerative Diseases. In: Sattler, R., Donnelly, C. (eds) RNA Metabolism in Neurodegenerative Diseases. Advances in Neurobiology, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-319-89689-2_4

Download citation

Publish with us

Policies and ethics

Search

Navigation