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000258679 1001_ $$aFodder, Katherine$$b0
000258679 245__ $$aBrain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes.
000258679 260__ $$aHeidelberg$$bSpringer$$c2023
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000258679 520__ $$aFrontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5'UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.
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000258679 650_7 $$2Other$$aCo-methylation
000258679 650_7 $$2Other$$aDNA methylation
000258679 650_7 $$2Other$$aEWAS
000258679 650_7 $$2Other$$aFrontotemporal dementia
000258679 650_7 $$2Other$$aHuman brain tissue
000258679 650_7 $$2Other$$aProgressive supranuclear palsy
000258679 650_7 $$09007-49-2$$2NLM Chemicals$$aDNA
000258679 650_7 $$2NLM Chemicals$$atau Proteins
000258679 650_7 $$0EC 3.4.19.12$$2NLM Chemicals$$aOTUD4 protein, human
000258679 650_7 $$0EC 3.4.19.12$$2NLM Chemicals$$aUbiquitin-Specific Proteases
000258679 650_2 $$2MeSH$$aHumans
000258679 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000258679 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: pathology
000258679 650_2 $$2MeSH$$aBrain: pathology
000258679 650_2 $$2MeSH$$aPick Disease of the Brain: pathology
000258679 650_2 $$2MeSH$$aDNA
000258679 650_2 $$2MeSH$$atau Proteins: metabolism
000258679 650_2 $$2MeSH$$aUbiquitin-Specific Proteases: metabolism
000258679 7001_ $$aMurthy, Megha$$b1
000258679 7001_ $$0P:(DE-2719)2810718$$aRizzu, Patrizia$$b2$$udzne
000258679 7001_ $$aToomey, Christina E$$b3
000258679 7001_ $$aHasan, Rahat$$b4
000258679 7001_ $$aHumphrey, Jack$$b5
000258679 7001_ $$aRaj, Towfique$$b6
000258679 7001_ $$aLunnon, Katie$$b7
000258679 7001_ $$aMill, Jonathan$$b8
000258679 7001_ $$0P:(DE-2719)2810728$$aHeutink, Peter$$b9$$udzne
000258679 7001_ $$aLashley, Tammaryn$$b10
000258679 7001_ $$00000-0001-9090-7690$$aBettencourt, Conceição$$b11
000258679 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-023-02583-z$$gVol. 146, no. 1, p. 77 - 95$$n1$$p77 - 95$$tActa neuropathologica$$v146$$x0001-6322$$y2023
000258679 8564_ $$uhttps://link.springer.com/article/10.1007/s00401-023-02583-z
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