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Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study

  • Olubankole Aladesuyi Arogundade
  • Jennifer E. Stauffer
  • Shahram Saberi
  • Sandra Diaz-Garcia
  • Sahana Malik
  • Hani Basilim
  • Maria J. Rodriguez
  • Takuya Ohkubo
  • John RavitsEmail author
Correspondence
  • 326 Downloads

Three main mechanisms are thought to contribute to neurodegeneration in C9ORF72 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD): toxicity from transcribed expanded repeat RNAs, toxicity from RAN-translated dipeptide repeat proteins (DPRs), and loss of C9ORF72 protein function [4, 5, 9, 11, 12, 18]. Sense and antisense RNA foci have both been consistently observed in C9-ALS/FTD neuropathology [1, 3, 5, 8, 9, 18] and hypothesized to cause neurodegeneration by sequestering critical RNA-binding proteins [2, 6]. Antisense, but not sense RNA foci have been shown to correlate with mislocalization of TDP-43, a signature protein of ALS and frontal–temporal lobar degeneration (FTLD) [1]. A unique circumferential studding of nucleoli by antisense RNA foci was observed in a case report of two C9-FTLD cases [17] and recently re-discussed with two additional cases [16]. Understanding the relative contributions from sense and antisense strands to pathogenesis is...

Notes

Acknowledgements

This research was supported by grants from ALS Association (5356S3), Target ALS (20134792), National Institute of Neurological Diseases and Stroke (NIH R01NS088578 and NS047101), and Pam Golden. OAA is supported by National Science Foundation Graduate Research Fellowship (DGE-1650112). TO is supported by NINDS CReATe Consortium (U54NS092091). Len Petrucelli provided extra sense probe for FISH. We thank the patients and their families for their generous contribution to this research.

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Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 52145 kb)

References

  1. 1.
    Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB et al (2015) Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol 130:63–75.  https://doi.org/10.1007/s00401-015-1429-9 CrossRefGoogle Scholar
  2. 2.
    Cooper-Knock J, Walsh MJ, Higginbottom A, Highley JR, Dickman MJ, Edbauer D et al (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137:2040–2051.  https://doi.org/10.1093/brain/awu120 CrossRefGoogle Scholar
  3. 3.
    DeJesus-Hernandez M, Finch NCA, Wang X, Gendron TF, Bieniek KF, Heckman MG et al (2017) In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers. Acta Neuropathol 134(2):255–269.  https://doi.org/10.1007/s00401-017-1725-7 CrossRefGoogle Scholar
  4. 4.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256.  https://doi.org/10.1016/j.neuron.2011.09.011 CrossRefGoogle Scholar
  5. 5.
    Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PEA, Caulfield T et al (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844.  https://doi.org/10.1007/s00401-013-1192-8 CrossRefGoogle Scholar
  6. 6.
    Haeusler AR, Donnelly CJ, Periz G, Simko EAJ, Shaw PG, Kim MS et al (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507(7491):195–200.  https://doi.org/10.1038/nature13124 CrossRefGoogle Scholar
  7. 7.
    Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T et al (2014) Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345(6201):1139–1145.  https://doi.org/10.1126/science.1254917 CrossRefGoogle Scholar
  8. 8.
    Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li H-R et al (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci 110(47):E4530–E4539.  https://doi.org/10.1073/pnas.1318835110 CrossRefGoogle Scholar
  9. 9.
    Mizielinska S, Lashley T, Norona FE, Clayton EL, Ridler CE, Fratta P et al (2013) C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol 126:845–857.  https://doi.org/10.1007/s00401-013-1200-z CrossRefGoogle Scholar
  10. 10.
    Mizielinska S, Ridler CE, Balendra R, Thoeng A, Woodling NS, Grässer FA et al (2017) Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathol Commun 5(1):29.  https://doi.org/10.1186/s40478-017-0432-x CrossRefGoogle Scholar
  11. 11.
    Mori K, Arzberger T, Grässer FA, Gijselinck I, May S, Rentzsch K et al (2013) Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126:881–893.  https://doi.org/10.1007/s00401-013-1189-3 CrossRefGoogle Scholar
  12. 12.
    Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268.  https://doi.org/10.1016/j.neuron.2011.09.010 CrossRefGoogle Scholar
  13. 13.
    Saberi S, Stauffer JE, Jiang J, Garcia SD, Taylor AE, Schulte D et al (2018) Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis. Acta Neuropathol 135(3):459–474.  https://doi.org/10.1007/s00401-017-1793-8 CrossRefGoogle Scholar
  14. 14.
    Schludi MH, May S, Grässer FA, Rentzsch K, Kremmer E, Küpper C et al (2015) Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol 130(4):537–555.  https://doi.org/10.1007/s00401-015-1450-z CrossRefGoogle Scholar
  15. 15.
    Tao Z, Wang H, Xia Q, Li K, Li K, Jiang X et al (2015) Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet 24:2426–2441.  https://doi.org/10.1093/hmg/ddv005 CrossRefGoogle Scholar
  16. 16.
    Vatsavayai SC, Nana AL, Yokoyama JS, Seeley WW (2018) C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies. Acta Neuropathol.  https://doi.org/10.1007/s00401-018-1921-0 (Epub ahead of print) Google Scholar
  17. 17.
    Vatsavayai SC, Yoon SJ, Gardner RC, Gendron TF, Vargas JNS, Trujillo A et al (2016) Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139(Pt 12):3202–3216CrossRefGoogle Scholar
  18. 18.
    Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J et al (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci 110(51):E4968–E4977.  https://doi.org/10.1073/pnas.1315438110 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Olubankole Aladesuyi Arogundade
    • 1
  • Jennifer E. Stauffer
    • 1
    • 2
  • Shahram Saberi
    • 1
    • 3
  • Sandra Diaz-Garcia
    • 1
  • Sahana Malik
    • 1
    • 4
  • Hani Basilim
    • 1
    • 5
  • Maria J. Rodriguez
    • 1
  • Takuya Ohkubo
    • 1
  • John Ravits
    • 1
    Email author
  1. 1.Department of NeuroscienceUniversity of California, San DiegoLa JollaUSA
  2. 2.The Jackson LaboratoryBar HarborUSA
  3. 3.Department of PathologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Cooper Medical School of Rowan UniversityCamdenUSA
  5. 5.King Abdullah Medical Complex Jeddah (KAMCJ)JiddaSaudi Arabia

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