Skip to main content
Springer Nature Link
Log in

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

  • Correspondence
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
€32.70 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Finland)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  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):3202–3216

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Jennifer E. Stauffer

    Present address: The Jackson Laboratory, 600 Main St, Bar Harbor, ME, 04609, USA

  2. Shahram Saberi

    Present address: Department of Pathology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1194, New York, NY, 10029, USA

  3. Sahana Malik

    Present address: Cooper Medical School of Rowan University, 401 South Broadway, Camden, NJ, 08103, USA

  4. Hani Basilim

    Present address: King Abdullah Medical Complex Jeddah (KAMCJ), Ameer Naif Road, Al-Shera’a, Jidda, 23816, Saudi Arabia

  5. Olubankole Aladesuyi Arogundade, Jennifer E. Stauffer and Shahram Saberi equal contributions.

Authors and Affiliations

  1. Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, MS-0624, La Jolla, CA, 92093, USA

    Olubankole Aladesuyi Arogundade, Jennifer E. Stauffer, Shahram Saberi, Sandra Diaz-Garcia, Sahana Malik, Hani Basilim, Maria J. Rodriguez, Takuya Ohkubo & John Ravits

Authors
  1. Olubankole Aladesuyi Arogundade
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer E. Stauffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shahram Saberi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandra Diaz-Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sahana Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hani Basilim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria J. Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takuya Ohkubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John Ravits
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Ravits.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 52145 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aladesuyi Arogundade, O., Stauffer, J.E., Saberi, S. et al. Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study. Acta Neuropathol 137, 527–530 (2019). https://doi.org/10.1007/s00401-018-01955-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-018-01955-0

Search

Navigation