Biology subjects

Bettencourt, C.

Publications and source records attributed to Bettencourt, C..

10 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

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↗

bioRxiv2023

Blood DDIT4 and TRIM13 transcript levels mark the early stages of Machado-Joseph disease

Machado-Joseph disease (MJD) is a rare late-onset polyglutamine neurodegenerative disease caused by the expansion of a CAG repeat in the ATXN3 gene encoding the ataxin- 3 (ATXN3) protein. Several studies have identified changes in the abundance of select transcripts and proteins in blood samples of MJD mutation carriers. Here, we aimed to: 1) identify blood transcriptional changes that could be potential biomarkers of MJD from preclinical to symptomatic disease stages; 2) correlate levels of differentially expressed transcripts in blood of MJD carriers with demographic, genetics, and clinical features; and 3) evaluate whether the identified differential abundance of selected transcripts in blood of MJD subjects is preserved in post-mortem brains of MJD patients. Using real- time quantitative PCR, we observed consistent dysregulation of DDIT4, TRIM13 and P2RY13 transcript levels in blood samples of MJD subjects from different disease stages (from preclinical to symptomatic), and of patients from two cohorts with different backgrounds (Azores and Brazil). Importantly, combined blood DDIT4 and TRIM13 transcript levels display a very high accuracy to discriminate MJD carriers in preclinical stage, early-stage patients, and patients with more than five years of disease duration from respective controls (AUC=1.00, AUC=0.96, and AUC=0.90, respectively). Moreover, in the combined group of Azorean and Brazilian patients, blood levels of P2RY13 transcript correlate with age at onset, and abundance of DDIT4 and TRIM13 transcripts correlate with the CAG repeat size of the expanded ATXN3 allele. In the subgroup of early-stage Azorean patients, blood levels of TRIM13 transcripts correlate with age at disease onset. Interestingly, abundance of DDIT4, TRIM13 and P2RY13 proteins is also altered in brains of MJD patients. In summary, this work shows that blood DDIT4 and TRIM13 transcript levels are potentially blood-based biomarkers of MJD of special usefulness in marking preclinical and early stages of the disease, and points for common dysregulated processes involving DDIT4, TRIM13 and P2RY13 in the blood and the brain of MJD subjects.

neuroscience↗

bioRxiv2023

Differential LRRK2 signalling and gene expression in WT-LRRK2 and G2019S-LRRK2 mouse microglia treated with zymosan and MLi2.

IntroductionMutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene cause autosomal dominant Parkinsons disease (PD) with the most common causative mutation being the LRRK2 p.G2019S within the kinase domain. LRRK2 protein is highly expressed in the human brain and also in the periphery, and high expression of dominant PD genes in immune cells suggest involvement of microglia and macrophages in inflammation related to PD. LRRK2 is known to respond to extracellular signalling including TLR4 resulting in alterations in gene expression, with the response to TLR2 signalling through zymosan being less known. MethodsHere, we investigated the effects of zymosan, a TLR2 agonist and the potent and specific LRRK2 kinase inhibitor MLi-2 on gene expression in microglia from LRRK2-WT and LRRK2 p.G2019S knock-in mice by RNA-Sequencing analysis. ResultsWe observed both overlapping and distinct zymosan and MLi-2 mediated gene expression profiles in microglia. At least two candidate Genome-Wide Association (GWAS) hits for PD, CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb), were notably downregulated by zymosan treatment. Genes involved in inflammatory response and nervous system development were up and downregulated respectively with zymosan treatment while MLi-2 treatment particularly exhibited upregulated genes for ion transmembrane transport regulation. Furthermore, we observed the top twenty most significantly differentially expressed genes in LRRK2 p.G2019S microglia show enriched biological processes in iron transport and response to oxidative stress. DiscussionOverall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis.

neuroscience↗

bioRxiv2023

Epigenetic age acceleration in frontotemporal lobar degeneration: a comprehensive analysis in the blood and brain

Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains to be one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.

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↗

bioRxiv2022

Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue

AimsEpigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter. MethodsWe analysed the performances of two DNA methylation-based clocks, DNAmClockMulti and DNAmClockCortical, in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and -synuclein aggregates in oligodendrocytes. ResultsEstimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClockCortical, r = [0.80-0.97], p<0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClockMulti significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClockCortica tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte-enriched cohorts (e.g., oligodendrocyte-enriched nuclei, p=6.1x10-5) suggested that this cell-type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClockCortica (r>0.31, p<0.05), and similar trends with DNAmClockMulti. Although increased age acceleration was observed in MSA compared to controls, no significant differences were observed upon adjustment for possible confounders (e.g., cell-type proportions). ConclusionsOur findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration.

neuroscience↗

bioRxiv2020

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC; n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type. We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for {beta}-amyloid related functional classes, including the known Alzheimers disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

genomics↗