Transcriptome-wide characterization of the frontal cortex in FTLD.

Abstract

Alterations in the RNA metabolism represent a key pathological event in FTLD. Despite this, no study has characterized the diversity of brain RNA species (coding, non-coding and small RNAs) using high-throughput sequencing approaches. Total and small RNA sequencing was performed to study all RNA species from the frontal cortex (BA46) of patients neuropathologically diagnosed with FTLD-TDP (without mutations in genes causing FTLD (n = 10)), FTLD-TDP associated with the C9orf72 repeat expansion (n = 11), FTLD-tau (n = 13, six of them carrying the p.P301L mutation in the MAPT gene) and 7 controls without neuropathological alterations in the same brain region. Changes in the expression of RNAs (both long and small) were identified and validated through qPCR. Interestingly, some of these alterations overlapped between neuropathological subtypes (such as CHI3L1 upregulation), while other reflected a specific signature of transcriptome alterations in each FTLD subgroup. Cell-type deconvolution and gene co-expression network analyses disclosed a distinct shift in particular neuropathological subgroups. Data integration identified clusters of genes which correlated with the expression of small RNAs and the proportion of cellular subpopulations, suggesting orchestrated responses. Our data reveal a set of alterations which might be used as surrogate biomarkers of the underlying FTLD neuropathological subtype during life or as novel therapeutic targets and provide insights into complex transcriptome changes occurring in the frontal cortex of FTLD patients.