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000279453 1001_ $$aRambarack, Naiomi$$b0
000279453 245__ $$aDNA methylation as a contributor to dysregulation of STX6 and other frontotemporal Lobar degeneration genetic risk-associated loci.
000279453 260__ $$aLondon$$bBiomed Central$$c2025
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000279453 520__ $$aFrontotemporal lobar degeneration (FTLD) represents a spectrum of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders. The two major FTLD pathological subgroups are FTLD-TDP and FTLD-tau. While the majority of FTLD cases are sporadic, heterogeneity also exists within the familial cases, typically involving mutations in MAPT, GRN or C9orf72, which is not fully explained by known genetic mechanisms. We sought to address this gap by investigating the effect of epigenetic modifications, specifically DNA methylation variation, on genes associated with FTLD genetic risk in different FTLD subtypes. We used frontal cortex DNA methylation profiles from three FTLD datasets containing different subtypes of FTLD-TDP and FTLD-tau: FTLD1m (N = 23) containing FTLD-TDP C9orf72 mutation carriers and sporadic cases, FTLD2m (N = 48) containing FTLD-Tau MAPT mutation carriers, FTLD-TDP GRN and C9orf72 mutation carriers, and FTLD3m (N = 163) sporadic FTLD-Tau (progressive supranuclear palsy - PSP) cases, and corresponding controls. We then leveraged FTLD transcriptomic and proteomic datasets to investigate possible downstream effects of DNA methylation changes. Our analysis revealed shared promoter region hypomethylation in STX6 across FTLD-TDP and FTLD-tau subtypes, though the largest effect size was observed in PSP cases compared to controls (delta-beta = -32%, FDR adjusted-p value = 0.002). We also observed dysregulation of the STX6 gene and protein expression in some FTLD subtypes. Additionally, we performed a detailed examination of MAPT, GRN and C9orf72 across subtypes and observed nominally significant differentially methylated CpGs in variable positions across the genes, often with unique patterns and downstream changes in gene/protein expression in mutation carriers. We highlight aberrant DNA methylation at different CpG sites mapping to genes previously associated with genetic risk of FTLD, including STX6. Our findings support convergence of genetic and epigenetic factors towards disruption of risk loci, bringing new insights into the contribution of these mechanisms to FTLD.
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000279453 650_7 $$2Other$$aDNA methylation
000279453 650_7 $$2Other$$aDisease risk
000279453 650_7 $$2Other$$aEpigenetics
000279453 650_7 $$2Other$$aFrontotemporal Lobar degeneration
000279453 650_7 $$2Other$$aFrontotemporal dementia
000279453 650_7 $$2Other$$aNeurodegeneration
000279453 650_7 $$2Other$$aProgressive supranuclear palsy
000279453 650_7 $$2NLM Chemicals$$aQa-SNARE Proteins
000279453 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000279453 650_7 $$2NLM Chemicals$$atau Proteins
000279453 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000279453 650_7 $$2NLM Chemicals$$aMAPT protein, human
000279453 650_7 $$2NLM Chemicals$$aProgranulins
000279453 650_2 $$2MeSH$$aHumans
000279453 650_2 $$2MeSH$$aDNA Methylation: genetics
000279453 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000279453 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000279453 650_2 $$2MeSH$$aMale
000279453 650_2 $$2MeSH$$aFemale
000279453 650_2 $$2MeSH$$aMiddle Aged
000279453 650_2 $$2MeSH$$aQa-SNARE Proteins: genetics
000279453 650_2 $$2MeSH$$aQa-SNARE Proteins: metabolism
000279453 650_2 $$2MeSH$$aAged
000279453 650_2 $$2MeSH$$aGenetic Predisposition to Disease: genetics
000279453 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000279453 650_2 $$2MeSH$$atau Proteins: genetics
000279453 650_2 $$2MeSH$$aMutation
000279453 650_2 $$2MeSH$$aProgranulins: genetics
000279453 7001_ $$aFodder, Katherine$$b1
000279453 7001_ $$aMurthy, Megha$$b2
000279453 7001_ $$aToomey, Christina$$b3
000279453 7001_ $$ade Silva, Rohan$$b4
000279453 7001_ $$0P:(DE-2719)2810728$$aHeutink, Peter$$b5
000279453 7001_ $$aHumphrey, Jack$$b6
000279453 7001_ $$aRaj, Towfique$$b7
000279453 7001_ $$aLashley, Tammaryn$$b8
000279453 7001_ $$aBettencourt, Conceição$$b9
000279453 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-025-02071-3$$gVol. 13, no. 1, p. 148$$n1$$p148$$tActa Neuropathologica Communications$$v13$$x2051-5960$$y2025
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