Improved detection of RNA foci in C9orf72 amyotrophic lateral sclerosis post-mortem tissue using BaseScope™ shows a lack of association with cognitive dysfunction

Arpan R. Mehta, Samantha K. Barton, Karina McDade, Sharon Abrahams, Siddharthan Chandran, Colin Smith* (Corresponding Author), Jenna Gregory* (Corresponding Author)

*Corresponding author for this work

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The C9orf72 hexanucleotide repeat expansion is the commonest known genetic mutation in amyotrophic lateral sclerosis. A neuropathological hallmark is the intracellular accumulation of RNA foci. The role that RNA foci play in the pathogenesis of amyotrophic lateral sclerosis is widely debated. Historically, C9orf72 RNA foci have been identified using in situ hybridization. Here, we have implemented BaseScope™, a high-resolution modified in situ hybridization technique. We demonstrate that previous studies have underestimated the abundance of RNA foci in neurons and glia. This improved detection allowed us to investigate the abundance, regional distribution and cell type specificity of sense C9orf72 RNA foci in post-mortem brain and spinal cord tissue of six deeply clinically phenotyped C9orf72 patients and six age- and sex-matched controls. We find a correlation between RNA foci and the accumulation of transactive response DNA-binding protein of 43 kDa in spinal motor neurons (rs = 0.93; P = 0.008), but not in glia or cortical motor neurons. We also demonstrate that there is no correlation between the presence of RNA foci and the accumulation of transactive response DNA binding protein of 43 kDa in extra-motor brain regions. Furthermore, there is no association between the presence of RNA foci and cognitive indices. These results highlight the utility of BaseScope™ in the clinicopathological assessment of the role of sense RNA foci in C9orf72.
Original languageEnglish
Article numberfcaa009
Number of pages10
JournalBrain Communications
Issue number1
Early online date31 Jan 2020
Publication statusPublished - Jan 2020

Bibliographical note

The authors would like to thank: (i) the Medical Research Council Edinburgh Brain Bank (ethics approval from East of Scotland Research Ethics Service, 16/ES/0084)) for supplying all post-mortem brain material and the Scottish Motor Neurone Disease Register (SMNDR)/Care Audit Research and Evaluation for Motor Neurone Disease (CARE-MND) consortium for all clinical and demographic data (ethical approval from Scotland A Research Ethics Committee 10/MRE00/78 and 15/SS/0216); (ii) The Scottish MND Clinical Specialist team for obtaining consent from patients with MND for inclusion in these studies; (iii) MND Scotland and the Sylvia Aitken Charitable Trust for funding CS to help to establish the MND Tissue Bank. The authors would also like to thank Advanced Cell Diagnostics for gifting the C9orf72 probe (BaseScopeTM Probe - BA-GGGGCCn-3zz-st, Cat Code: 704181), prior to it being made commercially


A.R.M. is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK. The Chandran laboratory is supported by the Euan MacDonald Centre and the UK Dementia Research Institute, which
receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.M.G. is funded by a starter grant for clinical lecturers from the Academy of Medical Sciences
(AMS: 210JMG 3102 R45620) and C.S. is supported by a Medical Research Council grant (MR/L016400/1).


  • sense RNA foci
  • cognition
  • TDP-43
  • C9orf72
  • ALS


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