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

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...



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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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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