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 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1200-z) contains supplementary material, which is available to authorized users.
Highlights
Frontotemporal lobar degeneration (FTLD) is a common cause of young-onset dementia [15, 24], characterised by atrophy of the frontal and temporal lobes
Quantification revealed GGGGCC sense RNA foci were specific to C9orf72 FTLD (C9FTLD) and occurred in 37 ± 3 % of neurons in the frontal cortex, 25 ± 5 % of granule cell neurons in the hippocampus, and 21 ± 6 % of granule cell neurons in the cerebellum (Fig. 1b)
We provide the first definitive evidence for the presence of both sense and antisense RNA foci in C9FTLD
Summary
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 has several neuropathological subtypes, the most common of which are cases with tau inclusions (FTLD-tau) and those with TDP-43-positive inclusions (FTLD-TDP) [7, 19]. C9orf cases fall into two of the four FTLD-TDP subtypes: FTLD-TDP type A, being characterised by many TDP-43-positive neuronal cytoplasmic inclusions and short dystrophic neurites, the majority of which are found in layer 2 of the cortex; or FLTD-TDP type B, characterised by moderate numbers of neuronal cytoplasmic inclusions
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