Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy

Pharmacological Research, Journal Year: 2024, Volume and Issue: 205, P. 107247 - 107247

Published: June 2, 2024

About 80% of brain disorders have a genetic basis. The pathogenesis most neurodegenerative diseases is associated with myriad defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. emergence new sequencing technologies tools to study the epigenome has led identifying predictive biomarkers for earlier diagnosis, opening up possibility prophylactical interventions. As result, advances in pharmacogenetics pharmacoepigenomics now allow personalized treatments based on profile each patient specific mechanisms involved. This Review highlights complexity variability responses pharmacotherapy, emphasizing influence polymorphisms pharmacokinetics pharmacodynamics drugs used treat those conditions. We specifically discuss potential modulatory effect several an increased risk developing different diseases. explore genomic analyzing individual-specific drug metabolism predict response clinical outcomes. also provide insights into mechanism action under investigation their impact disease-modifying pathways. Finally, underscores great this field enhance effectiveness safety through medicine.

Language: Английский

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The Role of Hydrogen Sulfide (H2S) in Epigenetic Regulation of Neurodegenerative Diseases: A Systematic Review

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12555 - 12555

Published: Aug. 8, 2023

This review explores the emerging role of hydrogen sulfide (H

Language: Английский

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An Epigenetic Manifestation of Alzheimer's Disease: DNA Methylation

Actas Españolas de Psiquiatría, Journal Year: 2024, Volume and Issue: 52(3), P. 365 - 374

Published: June 5, 2024

Alzheimer's disease (AD), the most common form of dementia, has a complex pathogenesis. The number AD patients increased in recent years due to population aging, while trend toward younger age onset arisen, imposing substantial burden on society and families, garnering extensive attention. DNA methylation recently been revealed play an important role progression. is critical mechanism regulating gene expression, alterations this dysregulate expression disrupt pathways, including oxidative stress responses, inflammatory reactions, protein degradation processes, eventually resulting disease. Studies have widespread changes patients' peripheral blood brain tissues, affecting multiple signaling pathways severely impacting neuronal cell synaptic functions. This review summarizes pathogenesis AD, aiming provide theoretical basis for its early prevention treatment.

Language: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Frontotemporal Lobar Degeneration (FTLD) represents a spectrum of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders characterised by progressive atrophy the frontal temporal lobes brain. The two major FTLD pathological subgroups are FTLD-TDP FTLD-tau. While majority cases sporadic, heterogeneity also exists within familial cases, typically involving mutations in MAPT, GRN or C9orf72, which is not fully explained known genetic mechanisms. We sought to address this gap investigating effect epigenetic modifications, specifically DNA methylation variation, on genes associated with risk different subtypes. compiled list using text-mining databases literature searches. Frontal cortex profiles were derived from three datasets containing FTLD-tau: FTLD1m (N = 23) type A C9orf72 mutation carriers TDP Type C sporadic FTLD2m 48) FTLD-Tau MAPT carriers, B FTLD3m 163) supranuclear palsy (PSP) corresponding controls. To investigate downstream effects further, we then leveraged transcriptomic proteomic for controls examine gene protein expression levels. Our analysis revealed shared promoter region hypomethylation STX6 across FTLD-tau subtypes, though largest size was observed PSP compared (delta-beta -32%, adjusted-p value=0.002). dysregulation Additionally, performed detailed examination subtypes without presence nominally significant differentially methylated CpGs variable positions genes, often unique patterns consequences gene/protein carriers. highlight contribution at regions regulating previously FTLD, including STX6. analysed relationship mechanism increase our understanding how these mechanisms interact FTLD.

Language: Английский

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Integrative Epigenomic Landscape of Alzheimer's Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Alzheimer’s disease (AD) brains are characterized by neuropathologic and biochemical changes that highly variable across individuals. Capturing epigenetic factors associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 measures (Braak stage, Thal phase, cerebral amyloid angiopathy score) brain levels five proteins (APOE, amyloid-β (Aβ)40, Aβ42, tau, p-tau) core to pathogenesis. Using a regional (rCpGm) approach, we identified 5,478 significant associations, 99.7% which were tau measures. Of the tau-associated rCpGms, 93 had concordant associations external datasets comprising 1,337 samples. Integrative transcriptome-methylome analyses uncovered 535 gene expression for these rCpGms. Genes concurrent perturbations enriched oligodendrocyte marker genes, including known risk genes such as BIN1 , myelination MYRF, MBP MAG previously implicated AD, well like LDB3 . further annotated top additional 6 single cell 2 bulk transcriptome from two other tauopathies, Pick’s progressive supranuclear palsy (PSP). Our findings support consistent rCpGm tauopathies tau-related phenotypes both tissue clusters. In summary, uncover integrative epigenomic landscape demonstrate common potential pathomechanism different tauopathies.

Language: Английский

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Epigenetics factors in schizophrenia: future directions for etiologic and therapeutic study approaches

Annals of General Psychiatry, Journal Year: 2025, Volume and Issue: 24(1)

Published: April 4, 2025

Schizophrenia is a complex, heterogeneous, and highly disabling severe mental disorder whose pathogenesis has not yet been fully elucidated. Epigenetics, as bridge between genetic environmental factors, plays an important role in the pathophysiology of schizophrenia. Over past decade, epigenetic-wide association studies have rapidly become branch psychiatric research, especially deciphering molecular mechanisms This review systematically analyzes recent advances epigenome-wide (EWAS) schizophrenia, focusing on technological developments. We synthesize findings from large-scale EWAS alongside emerging evidence DNA methylation patterns, histone modifications, regulatory networks, emphasizing their roles disease treatment responses. In addition, this provides prospective outlook, evaluating impact that developments may future With continuous advancement high-throughput sequencing technology increasing maturity big data analysis methods, epigenetics expected to significant early diagnosis, prognosis assessment even personalized

Language: Английский

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Distinctive cell‐free DNA methylation characterizes presymptomatic genetic frontotemporal dementia

Annals of Clinical and Translational Neurology, Journal Year: 2024, Volume and Issue: 11(3), P. 744 - 756

Published: March 1, 2024

Abstract Objective Methylation of plasma cell‐free DNA (cfDNA) has potential as a marker brain damage in neurodegenerative diseases such frontotemporal dementia (FTD). Here, we study methylation cfDNA presymptomatic and symptomatic carriers genetic FTD pathogenic variants, next to healthy controls. Methods was isolated from cross‐sectional 10 (4 C9orf72 , 4 GRN 2 MAPT ), 9 Genome‐wide determined using high‐resolution sequencing technique (MeD‐seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for (vs. controls carriers), reevaluated validation cohort (8 presymptomatic: 3 ; 26 symptomatic: 7 6 12 1 TARDBP 13 noncarriers families). Results Presymptomatic showed distinctive profile compared carriers. DMR enabled significantly differentiate ( p < 0.001) 0.001). In cohort, these differentiated ≤ 0.007) only. Transcription‐start‐site carriers, generally associated with gene downregulation, enriched genes involved ubiquitin‐dependent processes, while body methylation, upregulation, neuronal cell processes. Interpretation A characterizes stage FTD, could reflect death this stage.

Language: Английский

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

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: July 12, 2024

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

Language: Английский

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Effects of Pterostilbene on the Cell Division Cycle of a Neuroblastoma Cell Line

Nutrients, Journal Year: 2024, Volume and Issue: 16(23), P. 4152 - 4152

Published: Nov. 29, 2024

The "Cell Cycle Hypothesis" suggests that the abnormal re-entry of neurons into cell division cycle leads to neurodegeneration, a mechanism supported by in vitro studies on neuronal-like cells treated with hyperphosphorylating agent forskolin. Pterostilbene, bioavailable compound found foods such as blueberries and grapes, may exert neuroprotective effects could serve potential adjunct therapy for neurodegenerative diseases.

Language: Английский

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Implications of Hydrogen Sulfide in Epigenetic Controlling in Neurodegenerative Diseases: A Narrative Review

Clinical Pathology & Research Journal, Journal Year: 2024, Volume and Issue: 8(1), P. 1 - 13

Published: Jan. 1, 2024

Previously we had have reviewed various neurodegenerative diseases (NDD), inclusive of Alzheimer’s disease (AD), Parkinson’s (PD), as well Huntington’s (HD), role hydrogen sulfide (H2 S), in treatment different cancers breast cancer, glioma, hepatocellular carcinoma along with epigenetics Diabetic Kidney Disease (DKD), pregnancy. There by the objective this review is provision an exhaustive outline present research controlling epigenetic events correlated NDD. Here conducted a narrative utilizing search engine pubmed, google scholar; web science; embase; Cochrane library MeSH terms like (NDD); ; H2 S disease; sulfide; Epigenetics; DNA methylation; Histone post-translational modifications; protein acetylation; methylation from 2000 till 2023 December date. Emerging proof has initiated unravelling facets which impacts topography followed propagation NDD AD, PD), HD. possesses capacity modulating crucial machinery for instance methylation, histone modifications noncoding RNAs influencing gene expression cellular working germane to neuronal survival, neuroinflammation, synaptic plasticity. Thus it constructed how works form imperative actor amongst close-knit network possessing probability opening innovative therapeutic arena. Although considerable work done, still lot lacunae exist on exact molecular modes plausible repercussions H2S quantities/its downstream targets. Finally isolation future directions having using

Language: Английский

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