C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers

Abstract

A non-coding hexanucleotide repeat expansion (HRE) in C9orf72 is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) acting through a loss of function mechanism due to haploinsufficiency of C9orf72 or a gain of function mediated by aggregates of bidirectionally transcribed HRE-RNAs translated into di-peptide repeat (DPR) proteins. To fully understand regulation of C9orf72 expression we surveyed the C9orf72 locus using Cap Analysis of Gene Expression sequence data (CAGEseq). We observed C9orf72 was generally lowly expressed with the exception of a subset of myeloid cells, particularly CD14+ monocytes that showed up to seven fold higher expression as compared to central nervous system (CNS) and other tissues. The expression profile at the C9orf72 locus showed a complex architecture with differential expression of the transcription start sites (TSSs) for the annotated C9orf72 transcripts between myeloid and CNS tissues suggesting cell and/or tissue specific functions. We further detected novel TSSs in both the sense and antisense strand at the C9orf72 locus and confirmed their existence in brain tissues and CD14+ monocytes. Interestingly, our experiments showed a consistent decrease of C9orf72 coding transcripts not only in brain tissue and monocytes from C9orf72-HRE patients, but also in brains from MAPT and GRN mutation carriers together with an increase in antisense transcripts suggesting these could play a role in regulation of C9orf72. We found that the non-HRE related expression changes cannot be explained by promoter methylation but by the presence of the C9orf72-HRE risk haplotype and unknown functional interactions between C9orf72, MAPT and GRN.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0306-7) contains supplementary material, which is available to authorized users.

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

“…For example, microglia from presymptomatic mutSOD1 mice exhibit an antiinflammatory phenotype and attenuated innate immune response compared with microglia from symptomatic mice, which are proinflammatory and exhibit toxic properties (86,87). Similar findings were demonstrated in vitro (88), suggesting that an adaptive shift in functional microglial ing since C9orf72 is highly expressed in myeloid cells, which are critically important for antigen presentation and development of autoimmunity, and loss of C9orf72 led to lysosomal accumulation and hyperactive immune responses in bone marrow macrophages (106,(109)(110)(111). The studies of C9orf72-null mice showed variability in the degree of autoantibody production and autoimmune-mediated tissue injury, indicating an environmental influence from different housing conditions that contributed to the development of autoimmunity.…”

Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog

“…Prior studies have also detected high levels of C9orf72 expression in the cerebellum 23, 42 . Consistent with this work, we detected C9orf72 promoter activity in both Purkinje cells and cerebellar granule cells.…”

Antisense ncRNAs during early vertebrate development are divided in groups with distinct features

“…However, few of them are studied in detail and are shown to play a role in early development (7). Unsurprisingly, number of antisense RNAs are implicated in many diseases (47,(57)(58)(59).…”