Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis

Abstract

BackgroundIn frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition.We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes (MAPT, GRN, CHMP2B, CTSC, HLA-DRA, TMEM106B, C9orf72, VCP, UBQLN2, OPTN, TARDBP and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products.ResultsGene co-expression networks revealed that several FTD-genes (such as MAPT and GRN, CTSC and HLA-DRA, TMEM106B, and C9orf72, VCP, UBQLN2 and OPTN) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling (MAPT and GRN modules); ii) immune and lysosomal processes (CTSC and HLA-DRA modules), and; iii) protein meta/catabolism (C9orf72, VCP, UBQLN2 and OPTN, and TMEM106B modules). PPI analysis supported the results of the functional annotation and pathway analyses.ConclusionsThis work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD-genes interactors as targets for further mechanistic characterization in hypothesis driven cell biology work.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0085-4) contains supplementary material, which is available to authorized users.

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

“…41 Of note, the relevant pleiotropic SNPs that we found in the HLA and MAPT regions do appear to exert their effect by influencing expression changes in cis -genes involved in immune response, endolysosomal processes, intracellular vesicular trafficking and DNA/chromatin-associated metabolism, further supporting the notion of involvement of these processes in neurodegenerative disease, including FTD. 42 More work will be needed to further characterise our pleiotropic signals, which might hold promise in the future for developing global preventive and therapeutic strategies for FTD, AD and PD.…”

Brain activation in frontotemporal and Alzheimer’s dementia: a functional near-infrared spectroscopy study

“…The genetic, molecular, and neuropathological underpinnings of bvFTD have been increasingly unraveled in the last years [6, 7]. Genetic and molecular profiles with the most common variants of nucleinacid-binding proteins such as FUS, TDP-43, C9orf72, or Progranulin contribute only partly to diagnose bvFTD patients [8].…”

scLM: automatic detection of consensus gene clusters across multiple single-cell datasets

“…Co-expressed genes work in concert in biological pathways and processes [1–3]. Such genes are involved in crucial biological activities including immune cell activation [4, 5], cellular epithelial-mesenchymal transition (EMT) [6], and transcription factor-mediated gene regulatory networks and signaling pathways [7, 8].…”