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.
Highlights
In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis
We evaluated gene expression levels across different brain regions, assessed co-expression profiles and performed functional annotation and pathway analyses for the relevant modules (= we defined ‘relevant modules’ those modules containing one or more Frontotemporal dementia (FTD)-genes with hub status [1-q < 0.1] and/or module membership [MM] values > 0.5; see Methods section for details)
We investigated whether the observed gene clustering is supported by known protein-protein interactors (PPIs) of FTD-genes products to infer the potential extent of the translation of the regionalspecific co-expression patterns into the protein domain
Summary
In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. 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, C9orf, VCP, UBQLN2, OPTN, TARDBP and FUS) associated with FTD and we carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products. The FTLD-FUS cases do not have a clear genetic component, whilst the rare FTLD-UPS cases have been associated with variability in the charged multivesicular body protein 2B (CHMP2B) gene [3]. These features suggest that there is no unidirectional relationship between the genetics and the molecular pathology of FTD and that the observed pathological signatures result from complex molecular mechanisms
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