Biology subjects

Fodder, K.

Publications and source records attributed to Fodder, K..

6 recordsLinked to original sources

bioRxiv2026

Cross-disease genetic and epigenetic architecture of the MOBP locus shows convergence in ALS-PSP

BackgroundMyelin associated oligodendrocyte basic protein (MOBP) is an abundantly expressed oligodendrocyte gene. Genetic variation at the MOBP locus has been associated with risk for multiple neurodegenerative disorders, including progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Epigenetically, MOBP promoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). Although MOBP is thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders. MethodsWe assessed genetic overlap and colocalisation at the MOBP locus across multiple neurodegenerative diseases. Disease-associated signals were fine-mapped to prioritise putative causal variants, and the strongest signals were subsequently investigated using molecular quantitative trait loci and post-mortem brain tissue datasets. ResultsALS and PSP showed strong genetic association at MOBP, with highly overlapping associated variants and strong evidence that both diseases share the same causal signal. Overlap with frontotemporal dementia was weaker. Methylation quantitative trait locus colocalisation identified cg15069948, located near an exon junction within MOBP, as strongly colocalising with the ALS and PSP genetic risk signals. In PSP brain tissue, carriers of the rs1768208-T risk allele showed lower methylation at cg15069948. We additionally identified evidence for an interaction between rs1768208 genotype and cg15069948 methylation associated with altered MOBP 3' untranslated region architecture. ConclusionsThese findings identify a shared ALS/PSP genetic-epigenetic mechanism at MOBP that is distinct from promoter-associated dysregulation in MSA. Together, they position MOBP as a key oligodendrocyte regulatory locus with both shared and disea e-specific roles in neurodegeneration.

neuroscience↗

bioRxiv2025

Early oligodendrocyte dysfunction signature in Alzheimer's disease: Insights from DNA methylomics and transcriptomics

Much research into the aetiology of Alzheimers disease (AD) has focused on neuronal cell types, while studies on the contribution of glial cells, particularly oligodendrocytes (OLGs), are only starting to emerge. Altered brain DNA methylation, an epigenetic modification that provides the interplay between genetics and environmental cues to tightly regulate gene expression, is well documented in AD. Yet, cell-type-specific investigations remain limited. Here, we examine the role of DNA methylation and OLGs in AD, and how such changes may impact gene expression. We performed weighted-gene correlation network analysis (WGCNA) on multiple brain omics AD datasets across species: human DNA methylation data from 4 brain regions, human brain single-nuclei RNA sequencing data and mouse brain RNA sequencing data. We compared AD-associated network modules enriched for OLG genes across AD brain regions, as well as with other neurodegenerative disease DNA methylation datasets. We identified a DNA methylation signature associated with AD, enriched for OLGs, and preserved across brain regions representing early and late AD pathology stages. Genes within this signature showed altered expression in AD OLGs, confirming cell-type specificity and relevance to AD. This OLG signature was also preserved in transgenic mice with early A{beta} pathology and in other neurodegenerative diseases without A{beta} pathology. We reveal a consistent pattern of OLG dysfunction spanning early to late stages of AD, across DNA methylation and gene expression. Our findings highlight OLG-associated DNA methylation changes as important in AD pathogenesis, and possibly in other neurodegenerative diseases, opening new avenues for therapeutic development.

neuroscience↗

bioRxiv2025

Transcriptomic and pathological analysis of the hnRNP network reveals glial involvement in FTLD pathological subtypes

Frontotemporal dementia (FTD) is a neurodegenerative disorder with a strong heritable component. Frontotemporal lobar degeneration (FTLD) refers to the pathological changes seen in FTD, characterised by atrophy of the frontal and temporal lobes and the presence of abnormal protein inclusions. In the case of FTLD with hyperphosphorylated TDP-43 positive inclusions (FTLD-TDP), five pathological subtypes (A, B, C, D, and E) are observed based on the types and distribution of inclusions found in the brain. In all subtypes, there tends to be a large variability in the number of pathological inclusions observed between cases, with limited correlation to clinical manifestations. TDP-43 is an RNA binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family which along with other hnRNPs modulates multiple aspects of RNA processing. HnRNPs other than TDP-43 have been implicated in several neurological diseases, including ALS, FTLD-TDP, FTLD-FUS and Alzheimers disease. Multiple hnRNPs have been found in pathological inclusions in specific subtypes of FTLD-TDP, suggesting potential roles in the disease process. The role of the hnRNP network in FTLD disease pathogenesis, however, has not yet been investigated. This study aimed to comprehensively evaluate the presence and expression of hnRNP proteins in two pathological subtypes of sporadic FTLD-TDP (A and C) as well as the genetic form FTLD-TDP A C9orf72 using immunohistochemistry and gene expression analysis by single-nuclei RNA-sequencing. We found that there was great variability in frequency of TDP-43 pathology across and within FTLD-TDP pathological subtypes. Finally, our findings suggest that distinct global transcriptomic profiles may underlie the different pathological subtypes of FTLD-TDP. The most prominent transcriptomic changes were observed in oligodendrocytes and astrocytes, involving multiple hnRNPs across FTLD subtypes compared to controls. Transcriptomic co-expression analysis further revealed that glial clusters were more strongly associated with RNA processing dysfunction and contribute to disease classification. Together, these findings highlight the involvement of the hnRNP network and glial-specific RNA processing alterations in FTLD-TDP pathophysiology, offering new insight into the molecular distinctions between pathological subtypes and potential targets for future investigation.

neuroscience↗

bioRxiv2025

DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal lobar degeneration genetic risk-associated loci

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.

neuroscience↗

bioRxiv2024

DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson's disease, and progressive supranuclear palsy: A cross-comparative investigation

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by neuronal loss and gliosis, with oligodendroglial cytoplasmic inclusions (GCIs) containing -synuclein being the primary pathological hallmark. Clinical presentations of MSA overlap with other parkinsonian disorders such as Parkinsons disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported perturbations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate three parkinsonian diseases, MSA, PD, and PSP, to identify shared and disease-specific DNA methylation alterations in white matter. Genome-wide DNA methylation profiling of frontal lobe white matter of individuals with MSA (n=17), PD (n=17), and PSP (n=16) and controls (n=15), using the Illumina EPIC array, revealed substantial commonalities in DNA methylation perturbations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signalling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport. Our results highlight several shared DNA methylation perturbations and pathways indicative of converging molecular mechanisms contributing towards neurodegeneration in the white matter of all three parkinsonian diseases.

neuroscience↗

bioRxiv2022

Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 and CEBPZ in shared dysregulated signatures across pathological subtypes

Frontotemporal 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 Alzheimers disease and Parkinsons 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 (234 individuals), generated using the Illumina 450K or EPIC microarray. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, 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 (5UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. Additionally, 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.

neuroscience↗