The role of DNA methylation in progression of neurological disorders and neurodegenerative diseases as well as the prospect of using DNA methylation inhibitors as therapeutic agents for such disorders

Rasmi, Yousef; Shokati, Ameneh; Hassan, Amber; Aziz, Shiva Gholizadeh‐Ghaleh; Bastani, Sepideh; Jalali, Ladan; Moradi, Faeze; Alipour, Shahriar

doi:10.1016/j.ibneur.2022.12.002

Cited by 33 publications

(31 citation statements)

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“…Overall, our study uncovered cell autonomous and nonautonomous defects together with epigenetic dysregulation contributing to the neurodevelopmental defects in the Ohia HLHS mouse model. The mechanistic insights obtained support new avenues for therapy to improve neurodevelopmental outcome, such as with manipulation of the epigenome via diet or pharmacological intervention 77 . It is worth noting as mice with microcephaly or normal brain anatomy can have similar neurobehavioral deficits, more sophisticated functional brain imaging may be needed to fully assess the risk for adverse neurodevelopmental outcome.…”

Section: Discussionmentioning

confidence: 88%

Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease

Gabriel,

Yagi,

Tan

et al. 2023

Preprint

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BackgroundHypoplastic left heart syndrome (HLHS), a severe congenital heart disease, is associated with poor neurodevelopmental outcomes, microcephaly, reduced cortical brain volume, brain dysmaturation, and neurobehavioral disorders such as autism. The involvement of patient intrinsic factors was indicated, but the mechanism is largely unknown.MethodsOhiamice with HLHS causing mutations in chromatin modifier Sin3A-associated protein 130 (Sap130) and cell adhesion protein ProtocadherinA9 (Pcdha9)were investigated for brain abnormalities by histology, immunomicroscopy, and molecular profiling by RNAseq, Sap130 ChIPseq, and genome-wide methylome analysis. Additionally, adult viablePcdha9m/mandEmx1-cre:Sap130f/−mice with forebrain deletion ofSap130were examined by brain MRI and behavioral assessments.ResultsOhiamice have brain abnormalities comprising forebrain hypoplasia and microcephaly in conjunction with a cortical neurogenesis defect. This is associated with loss of intermediate progenitors due to mitotic arrest and apoptosis from multipolar spindle formation, a mechanism also observed in primary microcephaly. Brain RNAseq showed perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity and memory, and defects in neurovascular coupling indicating perturbation of brain-sparing cerebral autoregulation. Disease pathways recovered included autism, intellectual disability, and other neurobehavioral/neurological deficits. These same pathways were observed upon intersection of genes that are differentially expressed with those that are differentially methylated and also are ChIPseq targets of Sap130, suggesting the transcriptional changes are epigenetically regulated. Adult viable mice harboring either thePcdha9mutation or forebrain-specificSap130deletion showed similar learning/memory deficits and autism-like behavior, suggesting they act on convergent pathways.ConclusionsOur observations indicate the intrinsic factors contributing to the adverse neurodevelopmental outcome associated with HLHS involve spindle defects causing impaired corticoneurogenesis, and brain and behavioral deficits associated with perturbed epigenetic regulation of neurodevelopmental pathways.Novelty and SignificanceWhat is known?Hypoplastic left heart syndrome (HLHS), a severe congenital heart disease, is associated with adverse neurodevelopmental outcome attributable to patient intrinsic factors.Cortical neurogenesis defect with reduced brain volume and microcephaly are observed beginningin utero,suggesting a developmental etiology.Learning impairment and autism spectrum disorder are commonly observed in HLHS.What new information does this article contribute?TheOhiaHLHS mouse model exhibits neurodevelopmental deficits comprising microcephaly and cortical neurogenesis defects with loss of neural progenitors from multipolar spindle formation, as well as impaired neurovascular coupling.Molecular profiling showed disturbance of REST, transcriptional regulator of neural stem cells, and CREB signaling regulating synaptic plasticity, with neurobehavioral assessments of the mutant mice showing learning/memory and autism-like behavioral deficits.Intersection of transcriptome and DNA methylation analyses uncovered an epigenetic basis for the neurodevelopmental/neurobehavioral abnormalities,Analysis of an HLHS mouse model indicated patient intrinsic factors causing adverse neurodevelopment in HLHS are genetic and epigenetic in etiology. This may include a mitotic spindle defect that would not be rescued by in utero aortic valvuloplasty, and a defect in neurovascular coupling that is likely to reduce the efficacy of maternal hyperoxygenation. However, epigenetic therapy may provide a new avenue for treatment that should be explored.

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Section: Discussionmentioning

confidence: 88%

Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease

Gabriel,

Yagi,

Tan

et al. 2023

Preprint

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“…Among PD-related genes in the brain substantia area, ARSA ( Senkevich et al, 2023 ), KANSL1-AS1 ( Lona-Durazo et al, 2023 ), FAM47E ( Blauwendraat et al, 2019 ), and ARHGAP27 ( Saeed, 2018 ) have been reported to be risk loci that contribute to the development of PD. The genetic alteration among NMRN1 ( Fuchs et al, 2007 ), CRHR1 ( Cheng et al, 2020 ; Rasmi et al, 2023 ), and HLA-DRB1 ( Le Guen et al, 2023 ) in the brain cortex increased the risk of PD.…”

Section: Resultsmentioning

confidence: 99%

Joint-tissue integrative analysis identifies high-risk genes for Parkinson’s disease

Wu,

Zheng,

Liu

et al. 2024

Front. Neurosci.

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The loss of dopaminergic neurons in the substantia nigra and the abnormal accumulation of synuclein proteins and neurotransmitters in Lewy bodies constitute the primary symptoms of Parkinson’s disease (PD). Besides environmental factors, scholars are in the early stages of comprehending the genetic factors involved in the pathogenic mechanism of PD. Although genome-wide association studies (GWAS) have unveiled numerous genetic variants associated with PD, precisely pinpointing the causal variants remains challenging due to strong linkage disequilibrium (LD) among them. Addressing this issue, expression quantitative trait locus (eQTL) cohorts were employed in a transcriptome-wide association study (TWAS) to infer the genetic correlation between gene expression and a particular trait. Utilizing the TWAS theory alongside the enhanced Joint-Tissue Imputation (JTI) technique and Mendelian Randomization (MR) framework (MR-JTI), we identified a total of 159 PD-associated genes by amalgamating LD score, GTEx eQTL data, and GWAS summary statistic data from a substantial cohort. Subsequently, Fisher’s exact test was conducted on these PD-associated genes using 5,152 differentially expressed genes sourced from 12 PD-related datasets. Ultimately, 29 highly credible PD-associated genes, including CTX1B, SCNA, and ARSA, were uncovered. Furthermore, GO and KEGG enrichment analyses indicated that these genes primarily function in tissue synthesis, regulation of neuron projection development, vesicle organization and transportation, and lysosomal impact. The potential PD-associated genes identified in this study not only offer fresh insights into the disease’s pathophysiology but also suggest potential biomarkers for early disease detection.

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“…It is known that BDNF is a crucial cell survival element associated with a variety of brain diseases [14]. During development, it is vital for neuronal survival and differentiation, maturation of dendritic spine, and neuritic branching and connections [15].…”

Section: Discussionmentioning

confidence: 99%

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model

Chen¹,

Cai²,

Xu³

2023

Trop. J. Pharm Res

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Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway. Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting. Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p < 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats. Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

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The role of DNA methylation in progression of neurological disorders and neurodegenerative diseases as well as the prospect of using DNA methylation inhibitors as therapeutic agents for such disorders

Cited by 33 publications

References 158 publications

Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease

Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease

Joint-tissue integrative analysis identifies high-risk genes for Parkinson’s disease

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model

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