Transcriptome wide correlations with neuropathological hallmarks in the frontal cortex of FTLD patients

Abstract Background A key pathological event in frontotemporal lobar degeneration (FTLD) is the alteration of the RNA metabolism. Despite this, no study has characterized the diversity of RNA species using high‐throughput sequencing approaches and correlated them with the main neuropathological hallmarks across FTLD subtypes. Method Total and small RNA sequencing was performed in the frontal cortex of patients neuropathologically diagnosed with FTLD‐TDP (including non‐mutation carriers [sFTLD‐TDP;n = 9], and carriers of the C9orf72 repeat expansion [FTLD‐C9;n = 11]), FTLD‐tau (n = 13, six carrying the p.P301L mutation in MAPT ) and controls without neuropathological alterations in the same brain region (n = 7). Gene and miRNA co‐expression modules were identified using WGCNA. Cell‐type proportions were estimated through cell‐type deconvolution using MuSiC. Gene ontology enrichment analyses were performed using Metascape. We assessed in the frontal cortex the presence of pTDP43 (in sFTLD‐TDP and FTLD‐C9), dipeptide repeats and RNA foci (in FTLD‐C9), and tau aggregates (in FTLD‐tau) through quantitative immunohistochemistry and correlated their density with transcriptome‐wide RNA alterations. Result Our results indicate statistically significant correlations between gene and miRNA co‐expression modules, neuropathological changes and cell‐type proportions specific for each FTLD subtype. The most significant findings include: in sFTLD‐TDP, the density of pTDP43 positively correlated with a gene co‐expression module (R = 0.9,p = 0.04) enriched with splicing functions (p<1×10 −8 ), which directly correlated with a miRNA co‐expression module (R = 0.77,p = 5×10 −4 ) and the proportion of a microglial subpopulation (R = 0.69,p = 4×10 −3 ). In FTLD‐C9, the density of poly(GP) repeats inversely correlated with the proportion of a neuronal subpopulation (R = ‐0.62,p = 0.041), and negatively correlated with a gene co‐expression module (R = ‐0.67,p = 0.024) enriched with protein phosphorylation functions (p<1×10 −4 ). In FTLD‐tau, the density of tau aggregates negatively correlated with the proportion of a neuronal subpopulation (Fig.1A;R = ‐0.77,p = 0.003) and positively correlated with a miRNA (Fig.1B;R = 0.88,p = 8.8×10 −5 ) and a gene (Fig.1C;R = 0.65,p = 0.016) co‐expression module enriched in genes with neuron ensheathing functions (Fig.1D;p<1×10 −20 ). Conclusion Our data demonstrate selective vulnerability of cell‐subtypes to neuropathological changes. In addition, we describe striking correlations between the main neuropathological hallmarks of each FTLD subtype and specific gene and miRNA co‐expression modules, including their hub genes and miRNAs which might be used as biomarkers to identify the FTLD neuropathological substrate in vivo, and reveal novel molecular mechanisms amenable for therapeutic intervention in FTLD.