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@ARTICLE{Rambarack:279453,
      author       = {Rambarack, Naiomi and Fodder, Katherine and Murthy, Megha
                      and Toomey, Christina and de Silva, Rohan and Heutink, Peter
                      and Humphrey, Jack and Raj, Towfique and Lashley, Tammaryn
                      and Bettencourt, Conceição},
      title        = {{DNA} methylation as a contributor to dysregulation of
                      {STX}6 and other frontotemporal {L}obar degeneration genetic
                      risk-associated loci.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {13},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2025-00780},
      pages        = {148},
      year         = {2025},
      abstract     = {Frontotemporal 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.},
      keywords     = {Humans / DNA Methylation: genetics / Frontotemporal Lobar
                      Degeneration: genetics / Frontotemporal Lobar Degeneration:
                      metabolism / Male / Female / Middle Aged / Qa-SNARE
                      Proteins: genetics / Qa-SNARE Proteins: metabolism / Aged /
                      Genetic Predisposition to Disease: genetics / C9orf72
                      Protein: genetics / tau Proteins: genetics / Mutation /
                      Progranulins: genetics / DNA methylation (Other) / Disease
                      risk (Other) / Epigenetics (Other) / Frontotemporal Lobar
                      degeneration (Other) / Frontotemporal dementia (Other) /
                      Neurodegeneration (Other) / Progressive supranuclear palsy
                      (Other) / Qa-SNARE Proteins (NLM Chemicals) / C9orf72
                      Protein (NLM Chemicals) / tau Proteins (NLM Chemicals) /
                      C9orf72 protein, human (NLM Chemicals) / MAPT protein, human
                      (NLM Chemicals) / Progranulins (NLM Chemicals)},
      cin          = {AG Heutink},
      ddc          = {610},
      cid          = {I:(DE-2719)1210002},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40618089},
      doi          = {10.1186/s40478-025-02071-3},
      url          = {https://pub.dzne.de/record/279453},
}