C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci
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Original Paper
C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci Sarah Mizielinska · Tammaryn Lashley · Frances E. Norona · Emma L. Clayton · Charlotte E. Ridler · Pietro Fratta · Adrian M. Isaacs
Received: 6 September 2013 / Revised: 16 October 2013 / Accepted: 19 October 2013 / Published online: 30 October 2013 © The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Non-coding repeat expansions may cause disease by reducing the expression level of the gene they reside in, by producing toxic aggregates of repeat RNA termed RNA foci, or by producing toxic proteins generated by repeat-associated non-ATG translation. We present the first definitive report of C9orf72 repeat sense and antisense RNA foci using a series of C9FTLD cases, and neurodegenerative disease and normal controls. A sensitive and specific fluorescence in situ hybridisation protocol was combined with protein immunostaining to show that both sense and antisense foci were frequent, specific to C9FTLD, and present in neurons of the frontal cortex, hippocampus and cerebellum. High-resolution imaging also allowed accurate analyses of foci number and subcellular localisation. RNA foci were most abundant in the frontal cortex, where 51 % of neurons contained foci. RNA foci also occurred in Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1200-z) contains supplementary material, which is available to authorized users. S. Mizielinska · F. E. Norona · E. L. Clayton · C. E. Ridler · P. Fratta · A. M. Isaacs (*) Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK e-mail: [email protected] T. Lashley Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK P. Fratta MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
astrocytes, microglia and oligodendrocytes but to a lesser degree than in neurons. RNA foci were observed in both TDP-43- and p62-inclusion bearing neurons, but not at a greater frequency than expected by chance. RNA foci abundance in the frontal cortex showed a significant inverse correlation with age at onset of disease. These data establish that sense and antisense C9orf72 repeat RNA foci are a consistent and specific feature of C9FTLD, providing new insight into the pathogenesis of C9FTLD. Keywords FTLD · FTD · ALS · RNA foci · Antisense · C9orf72
Introduction Frontotemporal lobar degeneration (FTLD) is a common cause of young-onset dementia [15, 24], characterised by atrophy of the frontal and temporal lobes. The three major genetic causes of FTLD are mutations in MAPT [16, 23, 27], GRN [4, 9], and C9orf72 [10, 13, 25]. FTLD shares clinical, genetic and pathologi
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