TY  - JOUR
AU  - Rambarack, Naiomi
AU  - Fodder, Katherine
AU  - Murthy, Megha
AU  - Toomey, Christina
AU  - de Silva, Rohan
AU  - Heutink, Peter
AU  - Humphrey, Jack
AU  - Raj, Towfique
AU  - Lashley, Tammaryn
AU  - Bettencourt, Conceição
TI  - DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal Lobar degeneration genetic risk-associated loci.
JO  - Acta Neuropathologica Communications
VL  - 13
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DZNE-2025-00780
SP  - 148
PY  - 2025
AB  - 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
KW  - Humans
KW  - DNA Methylation: genetics
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Male
KW  - Female
KW  - Middle Aged
KW  - Qa-SNARE Proteins: genetics
KW  - Qa-SNARE Proteins: metabolism
KW  - Aged
KW  - Genetic Predisposition to Disease: genetics
KW  - C9orf72 Protein: genetics
KW  - tau Proteins: genetics
KW  - Mutation
KW  - Progranulins: genetics
KW  - DNA methylation (Other)
KW  - Disease risk (Other)
KW  - Epigenetics (Other)
KW  - Frontotemporal Lobar degeneration (Other)
KW  - Frontotemporal dementia (Other)
KW  - Neurodegeneration (Other)
KW  - Progressive supranuclear palsy (Other)
KW  - Qa-SNARE Proteins (NLM Chemicals)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Progranulins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40618089
DO  - DOI:10.1186/s40478-025-02071-3
UR  - https://pub.dzne.de/record/279453
ER  -