In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers

Mariely DeJesus-Hernandez, NiCole A. Finch, Xue Wang, Tania F. Gendron, Kevin F. Bieniek, Michael G. Heckman, Aliaksei Vasilevich, Melissa E. Murray, Linda Rousseau, Rachael Weesner, Anthony Lucido, Meeia Parsons, Jeannie Chew, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, Bradley F. Boeve, Neill R. Graff-Radford, Jan de BoerYan W. Asmann, Leonard Petrucelli, Kevin B. Boylan, Dennis W. Dickson, Marka van Blitterswijk*, Rosa Rademakers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

50 Citations (Web of Science)

Abstract

A growing body of evidence suggests that a loss of chromosome 9 open reading frame 72 (C9ORF72) expression, formation of dipeptide-repeat proteins, and generation of RNA foci contribute to disease pathogenesis in amyotrophic lateral sclerosis and frontotemporal dementia. Although the levels of C9ORF72 transcripts and dipeptide-repeat proteins have already been examined thoroughly, much remains unknown about the role of RNA foci in C9ORF72-linked diseases. As such, we performed a comprehensive RNA foci study in an extensive pathological cohort of C9ORF72 expansion carriers (n = 63). We evaluated two brain regions using a newly developed computer-automated pipeline allowing recognition of cell nuclei and RNA foci (sense and antisense) supplemented by manual counting. In the frontal cortex, the percentage of cells with sense or antisense RNA foci was 26 or 12%, respectively. In the cerebellum, 23% of granule cells contained sense RNA foci and 1% antisense RNA foci. Interestingly, the highest percentage of cells with RNA foci was observed in cerebellar Purkinje cells (similar to 70%). In general, more cells contained sense RNA foci than antisense RNA foci; however, when antisense RNA foci were present, they were usually more abundant. We also observed that an increase in the percentage of cells with antisense RNA foci was associated with a delayed age at onset in the frontal cortex (r = 0.43, p = 0.003), whereas no other associations with clinico-pathological features were seen. Importantly, our large-scale study is the first to provide conclusive evidence that RNA foci are not the determining factor of the clinico-pathological variability observed in C9ORF72 expansion carriers and it emphasizes that the distribution of RNA foci does not follow the pattern of neurodegeneration, stressing the complex interplay between different aspects of C9ORF72-related diseases.

Original languageEnglish
Pages (from-to)255-269
Number of pages15
JournalActa Neuropathologica
Volume134
Issue number2
DOIs
Publication statusPublished - Aug 2017

Keywords

  • C9ORF72
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Motor neuron disease
  • Amyotrophic lateral sclerosis
  • RNA foci
  • DIPEPTIDE-REPEAT PROTEINS
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • BAC TRANSGENIC MICE
  • HEXANUCLEOTIDE REPEAT
  • PATHOLOGICAL FEATURES
  • ANTISENSE TRANSCRIPTS
  • NEURONAL LOSS
  • ALS/FTD
  • ALS
  • TOXICITY

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