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Background Existing treatments for asthma are not effective in all patients and disease exacerbations are common, highlighting the need for increased understanding of disease mechanisms and novel treatment strategies. The leukotriene pathway including the enzyme responsible for arachidonic acid release from cellular phospholipids, cPLA2α, is a major contributor to asthmatic responses and an attractive target in asthma therapies. Objective The study reported here investigates (a) the differential effects of in vitro exposure of peripheral blood mononuclear cells (PBMCs) to allergen between asthma and healthy subjects, and (b) the contribution of cPLA2α to these differences in gene expression. Methods In vitro responses of asthma ( N=26) and healthy ( N=11) subject PBMC samples to allergen stimulation in the presence and absence of cPLA2α inhibition or 5-lipoxygenase inhibition were compared at the gene expression level using oligonucleotide arrays and at the protein level using ELISA. Results Subject samples within both asthma and healthy groups showed allergen-dependent cytokine production and allergen-dependent gene expression changes, although transcriptional profiling identified 153 genes that were modulated significantly differently by allergen between asthma and healthy subjects. Among these were genes previously associated with asthma, but the majority (about 80%) have not previously been associated with asthma. Conclusions Transcriptional profiling elucidated novel gene expression differences between the asthmatic and healthy subject samples. Although 5-lipoxygenase inhibition did not significantly affect allergen-modulated gene expression, the inhibition of cPLA2α activity affected many of the allergen-dependent, asthma-associated gene expression changes. [ABSTRACT FROM AUTHOR]

RATIONALE: IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma. AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways. OBJECTIVES: To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma. METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, patients received weekly subcutaneous injections of placebo or AMG 317 (75-300 mg) for 12 weeks, followed by a 4-week follow-up period. The primary endpoint was change from baseline at Week 12 in Asthma Control Questionnaire (ACQ) symptom score. MEASUREMENTS AND MAIN RESULTS: Mean ACQ change (SE) was -0.49 (0.09) in placebo (n = 74), and -0.43 (0.11), -0.58 (0.12), and -0.70 (0.09) in the AMG 317 75 mg (n = 73), 150 mg (n = 73), and 300 mg (n = 74) groups, respectively (treatment effect P = 0.25). No statistically significant differences were observed in the secondary endpoints. Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg. Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores (>or=2.86) were more likely to respond to AMG 317. Serious adverse events were reported in three patients, each noted as not related to study drug. CONCLUSIONS: AMG 317 did not demonstrate clinical efficacy across the overall group of patients. Clinically significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores. AMG 317 was safe and well tolerated in this study population. Clinical trial registered with www.clinicaltrials.gov (NCT 00436670). [ABSTRACT FROM AUTHOR]

BACKGROUND: Emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution are 2 topical antiallergic agents available in the United States and other countries. Emedastine is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. Ketotifen is indicated for the temporary relief of ocular itching caused by allergic conjunctivitis. OBJECTIVE: The purpose of this study was to compare the efficacy of these agents in the temporary relief of ocular itching due to allergic conjunctivitis. The 2 agents were compared with each other and with placebo (artificial tears) using the conjunctival allergen challenge (CAC) model. METHODS: This was a single-center, randomized, double-masked, placebo-controlled study. At visit 1, CAC was performed on eligible subjects to identify the dose required to elicit a positive allergic reaction. Subjects returned after 7 days for visit 2 to confirm the allergen dose. On day 14 (+/-3) of the study, enrolled subjects were randomized to 1 of 3 treatment groups: emedastine in I eye and placebo in the other, ketotifen in 1 eye and placebo in the other, or emedastine in 1 eye and ketotifen in the other. In 25 subjects, bilateral CAC was performed 5 minutes after study medication instillation. In a second group of 20 subjects, CAC was performed 15 minutes after medication instillation. Itching was graded according to a standardized 5-point scale (0 = none to 4 = severe itching) at 3, 5, and 10 minutes postchallenge. Differences in efficacy scores between treatments and versus placebo were compared using 2-sample t tests of equal variance. RESULTS: A total of 45 patients (mean age, 41.2 years) received treatment: 16 received emedastine in 1 eye and ketotifen in the other; 14 received emedastine in 1 eye and placebo in the other; and 15 received ketotifen in 1 eye and placebo in the other. Both emedastine and ketotifen significantly inhibited itching (P < 0.05) compared with placebo at all time points after the 5- and 15-minute CAC. Mean raw scores for the active treatments were not statistically different. The mean itching efficacy scores were also not statistically different between active treatments. No adverse events were reported in this study. CONCLUSION: The results of this study suggest that emedastine and ketotifen are not significantly different with respect to anti-itching efficacy in the CAC model of acute allergic conjunctivitis. [ABSTRACT FROM AUTHOR]

Gliomas, highly aggressive tumors of the central nervous system, present overwhelming challenges due to their heterogeneity and therapeutic resistance. Glioblastoma multiforme (GBM), the most malignant form, underscores this clinical urgency due to dismal prognosis despite aggressive treatment regimens. Recent advances in cancer research revealed signaling pathways and epigenetic mechanisms that intricately govern glioma progression, offering multifaceted targets for therapeutic intervention. This review explores the dynamic interplay between signaling events and epigenetic regulation in the context of glioma, with a particular focus on the crucial roles played by non-coding RNAs (ncRNAs). Through direct and indirect epigenetic targeting, ncRNAs emerge as key regulators shaping the molecular landscape of glioblastoma across its various stages. By dissecting these intricate regulatory networks, novel and patient-tailored therapeutic strategies could be devised to improve patient outcomes with this devastating disease.

According to a growing body of neurobiological evidence, the core symptoms of borderline personality disorder (BPD) may be linked to an opioidergic imbalance between the hedonic and stimulatory activity of mu opioid receptors (MOR) and the reward system inhibiting effects of kappa opioid receptors (KOR). Childhood trauma (CT), which is etiologically relevant to BPD, is also likely to lead to epigenetic and neurobiological adaptations by extensive activation of the stress and endogenous opioid systems. In this study, we investigated the methylation differences in the promoter of the KOR gene (OPRK1) in subjects with BPD (N = 47) and healthy controls (N = 48). Comparing the average methylation rates of regulatorily relevant subregions (specified regions CGI-1, CGI-2, EH1), we found no differences between BPD and HC. Analyzing individual CG nucleotides (N = 175), we found eight differentially methylated CG sites, all of which were less methylated in BPD, with five showing highly interrelated methylation rates. This differentially methylated region (DMR) was found on the falling slope (5') of the promoter methylation gap, whose effect is enhanced by the DMR hypomethylation in BPD. A dimensional assessment of the correlation between disease severity and DMR methylation rate revealed DMR hypomethylation to be negatively associated with BPD symptom severity (measured by BSL-23). Finally, analyzing the influence of CT on DMR methylation, we found DMR hypomethylation to correlate with physical and emotional neglect in childhood (quantified by CTQ). Thus, the newly identified DMR may be a biomarker of the risks caused by CT, which likely epigenetically contribute to the development of BPD., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The physiological performance of any sensory organ is determined by its anatomy and physical properties. Consequently, complex sensory structures with elaborate features have evolved to optimize stimulus detection. Understanding these structures and their physical nature forms the basis for mechanistic insights into sensory function. Despite its crucial role as a sensor for pheromones and other behaviorally instructive chemical cues, the vomeronasal organ (VNO) remains a poorly characterized mammalian sensory structure. Fundamental principles of its physico-mechanical function, including basic aspects of stimulus sampling, remain poorly explored. Here, we revisit the classical vasomotor pump hypothesis of vomeronasal stimulus uptake. Using advanced anatomical, histological, and physiological methods, we demonstrate that large parts of the lateral mouse VNO are composed of smooth muscle. Vomeronasal smooth muscle tissue comprises two subsets of fibers with distinct topography, structure, excitation-contraction coupling, and, ultimately, contractile properties. Specifically, contractions of a large population of noradrenaline-sensitive cells mediate both transverse and longitudinal lumen expansion, whereas cholinergic stimulation targets an adluminal group of smooth muscle fibers. The latter run parallel to the VNO's rostro-caudal axis and are ideally situated to mediate antagonistic longitudinal constriction of the lumen. This newly discovered arrangement implies a novel mode of function. Single-cell transcriptomics and pharmacological profiling reveal the receptor subtypes involved. Finally, 2D/3D tomography provides non-invasive insight into the intact VNO's anatomy and mechanics, enables measurement of luminal fluid volume, and allows an assessment of relative volume change upon noradrenergic stimulation. Together, we propose a revised conceptual framework for mouse vomeronasal pumping and, thus, stimulus sampling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose of Review: A modified Delphi process was undertaken to provide a US expert-led consensus to guide clinical action on short-acting beta 2 -agonist (SABA) use. This comprised an online survey (Phase 1), forum discussion and statement development (Phase 2), and statement adjudication (Phase 3)., Recent Findings: In Phase 1 (n = 100 clinicians), 12% routinely provided patients with ≥4 SABA prescriptions/year, 73% solicited SABA use frequency at every patient visit, and 21% did not consult asthma guidelines/expert reports. Phase 3 experts (n = 8) reached consensus (median Likert score, interquartile range) that use of ≥3 SABA canisters/year is associated with increased risk of exacerbation and asthma-related death (5, 4.75-5); SABA use history should be solicited at every patient visit (5, 4.75-5); usage patterns over time, not absolute thresholds, should guide response to SABA overuse (5, 4.5-5). Future asthma guidelines should include clear recommendations regarding SABA usage, using expert-led thresholds for action., (© 2023. The Author(s).)

Cell-cell communication is mediated by membrane receptors and their ligands, such as the Eph/ephrin system, orchestrating cell migration during development and in diverse cancer types. Epigenetic mechanisms are key for integrating external "signals", e.g., from neighboring cells, into the transcriptome in health and disease. Previously, we reported ephrinA5 to trigger transcriptional changes of lncRNAs and protein-coding genes in cerebellar granule cells, a cell model for medulloblastoma. LncRNAs represent important adaptors for epigenetic writers through which they regulate gene expression. Here, we investigate a lncRNA-mediated targeting of DNMT1 to specific gene loci by the combined power of in silico modeling of RNA/DNA interactions and wet lab approaches, in the context of the clinically relevant use case of ephrinA5-dependent regulation of cellular motility of cerebellar granule cells. We provide evidence that Snhg15, a cancer-related lncRNA, recruits DNMT1 to the Ncam1 promoter through RNA/DNA triplex structure formation and the interaction with DNMT1. This mediates DNA methylation-dependent silencing of Ncam1, being abolished by ephrinA5 stimulation-triggered reduction of Snhg15 expression. Hence, we here propose a triple helix recognition mechanism, underlying cell motility regulation via lncRNA-targeted DNA methylation in a clinically relevant context., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Long noncoding RNAs (lncRNAs) are a regulatory class of noncoding RNAs with a wide range of activities such as transcriptional and post-transcriptional regulations. Emerging evidence has demonstrated that various lncRNAs contribute to the initiation and progression of Rheumatoid Arthritis (RA) through distinctive mechanisms. The present study reviews the recent findings on lncRNA role in RA development. It focuses on the involvement of different lncRNAs in the main steps of RA pathogenesis including T cell activation, cytokine dysregulation, fibroblast-like synoviocyte (FLS) activation and joint destruction. Besides, it discusses the current findings on RA diagnosis and the potential of lncRNAs as diagnostic, prognostic and predictive biomarkers in Rheumatology clinic., Competing Interests: Declaration of competing interest All authors of the manuscript PBMB-D-22-00021 declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

DNA methyltransferases (DNMTs) are widely expressed in the brain, dictating the transcriptional activity of genes through various epigenetic mechanisms. Functional irregularities, alterations in the activity, and aberrant expression levels of DNMTs have been linked to various neurodevelopmental abnormalities, neuropsychiatric disorders, neurodegenerative diseases, and brain cancer. A continuously increasing number of studies address the roles DNMTs have in the brain, to reach a better understanding of their involvement in disease-related pathophysiologies, which in turn is required to dissect their applicability as potential therapeutic targets. This chapter provides an overview of DNMT function in the developing and the adult brain, putting a spotlight on their role in orchestrating diverse aspects of brain development, memory, and aging, followed by a discussion of associated neurodevelopmental and neurodegenerative disorders, and the implications in brain cancer., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Competing Interests: None

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer's Disease, are a scourge of the aging society, and in the case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here, we review current knowledge of tauopathies listing known genetic and important sporadic forms of these disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer's, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tools and usages of epigenetic therapy strategies for these diseases.

Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood. To approach how the different development-associated neuropathologies can occur and which risk factors or critical processes are involved in provoking higher susceptibility for such diseases, a detailed understanding of the mechanisms underlying proper brain formation is required. NDDs rely on deficits in neuronal identity, proportion or function, whereby a defective development of the cerebral cortex, the seat of higher cognitive functions, is implicated in numerous disorders. Such deficits can be provoked by genetic and environmental factors during corticogenesis. Thereby, epigenetic mechanisms can act as an interface between external stimuli and the genome, since they are known to be responsive to external stimuli also in cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, as well as regulatory non-coding RNAs regulate diverse aspects of neuronal development, and alterations in epigenomic marks have been associated with NDDs of varying phenotypes. Here, we provide an overview of essential steps of mammalian corticogenesis, and discuss the role of epigenetic mechanisms assumed to contribute to pathophysiological aspects of NDDs, when being disrupted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Reichard and Zimmer-Bensch.)

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.

Epigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activity in excitatory and inhibitory cortical neurons in mice. Since DNA methylation signatures are responsive to neuronal activity, DNA methylation seems to contribute to the neuron's capacity to adapt to and integrate changing activity patterns, being crucial for the plasticity and functionality of neuronal circuits. Since most studies addressing the role of DNA methylation in the regulation of synaptic function were conducted in mice or murine neurons, we here asked whether this functional implication applies to human neurons as well. To this end, we performed calcium imaging in human induced pluripotent stem cell (iPSC)-derived excitatory cortical neurons forming synaptic contacts and neuronal networks in vitro. Treatment with DNMT1 siRNA that diminishs the expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) was conducted to investigate the functional relevance of DNMT1 as one of the main enzymes executing DNA methylations in the context of neuronal activity modulation. We observed a lowered proportion of actively firing neurons upon DNMT1 -knockdown in these iPSC-derived excitatory neurons, pointing to a correlation of DNMT1-activity and synaptic transmission. Thus, our experiments suggest that DNMT1 decreases synaptic activity of human glutamatergic neurons and underline the relevance of epigenetic regulation of synaptic function also in human excitatory neurons.

During brain development, progenitors generate successive waves of neurons that populate distinct cerebral regions, where they settle and differentiate within layers or nuclei. While migrating and differentiating, neurons are subjected to mechanical forces arising from the extracellular matrix, and their interaction with neighboring cells. Changes in brain biomechanical properties, during its formation or aging, are converted in neural cells by mechanotransduction into intracellular signals that control key neurobiological processes. Here, we summarize recent findings that support the contribution of mechanobiology to neurodevelopment, with focus on the cerebral cortex. Also discussed are the existing toolbox and emerging technologies made available to assess and manipulate the physical properties of neurons and their environment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma.

Apart from the conventional view of repressive promoter methylation, the DNA methyltransferase 1 (DNMT1) was recently described to modulate gene expression through a variety of interactions with diverse epigenetic key players. We here investigated the DNMT1-dependent transcriptional control of the homeobox transcription factor LHX1, which we previously identified as an important regulator in cortical interneuron development. We found that LHX1 expression in embryonic interneurons originating in the embryonic pre-optic area (POA) is regulated by non-canonic DNMT1 function. Analysis of histone methylation and acetylation revealed that both epigenetic modifications seem to be implicated in the control of Lhx1 gene activity and that DNMT1 contributes to their proper establishment. This study sheds further light on the regulatory network of cortical interneuron development including the complex interplay of epigenetic mechanisms.

Neuropsychiatric diseases, such as mood disorders, schizophrenia, and autism, represent multifactorial disorders, differing in causes, disease onset, severity, and symptoms. A common feature of numerous neuropsychiatric conditions are defects in the cortical inhibitory GABAergic system. The balance of excitation and inhibition is fundamental for proper and efficient information processing in the cerebral cortex. Thus, altered inhibition is suggested to account for pathological symptoms like cognitive impairments and dysfunctional multisensory integration. While it became apparent that most of these diseases have a clear genetic component, environmental influences emerged as an impact of disease manifestation, onset, and severity. Epigenetic mechanisms of transcriptional control, such as DNA methylation, are known to be responsive to external stimuli, and are suspected to be implicated in the functional impairments of GABAergic interneurons, and hence, the pathophysiology of neuropsychiatric diseases. Here, we provide an overview about the multifaceted functional implications of DNA methylation and DNA methyltransferases in cortical interneuron development and function in health and disease. Apart from the regulation of gamma-aminobutyric acid-related genes and genes relevant for interneuron development, we discuss the role of DNA methylation-dependent regulation of synaptic transmission by the modulation of endocytosis-related genes as potential pathophysiological mechanisms underlying neuropsychiatric conditions. Deciphering the hierarchy and mechanisms of changes in epigenetic signatures is crucial to develop effective strategies for treatment and prevention., (Copyright © 2020 Linde and Zimmer-Bensch.)

In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of the diseases. Some of these disorders, like Huntington's disease (HD), rely on defined genetic factors. HD, as an incurable, fatal hereditary neurodegenerative disorder characterized by its mid-life onset, is caused by the expansion of CAG trinucleotide repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Apart from the genetic defect, environmental factors are thought to influence the risk, onset and progression of HD. As epigenetic mechanisms are known to readily respond to environmental stimuli, they are proposed to play a key role in HD pathogenesis. Indeed, dynamic epigenomic remodeling is observed in HD patients and in brains of HD animal models. Epigenetic signatures, such as DNA methylation, histone variants and modifications, are known to influence gene expression and to orchestrate various aspects of neuronal physiology. Hence, deciphering their implication in HD pathogenesis might open up new paths for novel therapeutic concepts, which are discussed in this review.

The limited regenerative capacity of neurons requires a tightly orchestrated cell death and survival regulation in the context of longevity, as well as age-associated and neurodegenerative diseases. Subordinate to genetic networks, epigenetic mechanisms, such as DNA methylation and histone modifications, are involved in the regulation of neuronal functionality and emerge as key contributors to the pathophysiology of neurodegenerative diseases. DNA methylation, a dynamic and reversible process, is executed by DNA methyltransferases (DNMTs). DNMT1 was previously shown to act on neuronal survival in the aged brain, whereby a DNMT1-dependent modulation of processes relevant for protein degradation was proposed as an underlying mechanism. Properly operating proteostasis networks are a mandatory prerequisite for the functionality and long-term survival of neurons. Malfunctioning proteostasis is found, inter alia, in neurodegenerative contexts. Here, we investigated whether DNMT1 affects critical aspects of the proteostasis network by a combination of expression studies, live cell imaging, and protein biochemical analyses. We found that DNMT1 negatively impacts retrograde trafficking and autophagy, with both being involved in the clearance of aggregation-prone proteins by the aggresome-autophagy pathway. In line with this, we found that the transport of GFP-labeled mutant huntingtin (HTT) to perinuclear regions, proposed to be cytoprotective, also depends on DNMT1. Depletion of Dnmt1 accelerated perinuclear HTT aggregation and improved the survival of cells transfected with mutant HTT. This suggests that mutant HTT-induced cytotoxicity is at least in part mediated by DNMT1-dependent modulation of degradative pathways.

Increased life expectancy in modern society comes at the cost of age-associated disabilities and diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-related disorders. Molecular mechanisms that exert epigenetic control of gene expression contribute to age-associated neuronal impairments. Both DNA methylation, mediated by DNA methyltransferases (DNMTs), and histone modifications maintain neuronal function throughout lifespan. Here we provide evidence that DNMT1 function is implicated in the age-related loss of cortical inhibitory interneurons. Dnmt1 deletion in parvalbumin-positive interneurons attenuates their age-related decline in the cerebral cortex. Moreover, conditional Dnmt1 -deficient mice show improved somatomotor performance and reduced aging-associated transcriptional changes. A decline in the proteostasis network, responsible for the proper degradation and removal of defective proteins, is implicated in age- and disease-related neurodegeneration. Our data suggest that DNMT1 acts indirectly on interneuron survival in aged mice by modulating the proteostasis network during life-time., (Copyright © 2020 Hahn, Pensold, Bayer, Tittelmeier, González-Bermúdez, Marx-Blümel, Linde, Groß, Salinas-Riester, Lingner, von Maltzahn, Spehr, Pieler, Urbach and Zimmer-Bensch.)

The balance of excitation and inhibition is essential for cortical information processing, relying on the tight orchestration of the underlying subcellular processes. Dynamic transcriptional control by DNA methylation, catalyzed by DNA methyltransferases (DNMTs), and DNA demethylation, achieved by ten-eleven translocation (TET)-dependent mechanisms, is proposed to regulate synaptic function in the adult brain with implications for learning and memory. However, focus so far is laid on excitatory neurons. Given the crucial role of inhibitory cortical interneurons in cortical information processing and in disease, deciphering the cellular and molecular mechanisms of GABAergic transmission is fundamental. The emerging relevance of DNMT and TET-mediated functions for synaptic regulation irrevocably raises the question for the targeted subcellular processes and mechanisms. In this study, we analyzed the role dynamic DNA methylation has in regulating cortical interneuron function. We found that DNMT1 and TET1/TET3 contrarily modulate clathrin-mediated endocytosis. Moreover, we provide evidence that DNMT1 influences synaptic vesicle replenishment and GABAergic transmission, presumably through the DNA methylation-dependent transcriptional control over endocytosis-related genes. The relevance of our findings is supported by human brain sample analysis, pointing to a potential implication of DNA methylation-dependent endocytosis regulation in the pathophysiology of temporal lobe epilepsy, a disease characterized by disturbed synaptic transmission., (© The Author(s) 2020. Published by Oxford University Press.)