Accumulation of alpha‐synuclein protein aggregates is the hallmark neuropathologic feature of synucleinopathies such as Parkinson’s disease. Rare point mutations and multiplications in SNCA, the gene ...encoding alpha‐synuclein, as well as other genetic alterations are linked to familial Parkinson’s disease cases with high penetrance and hence constitute major genetic risk factors for Parkinson’s disease. However, the preponderance of cases seems sporadic, most likely based on a complex interplay between genetic predispositions, aging processes and environmental influences. Deciphering the impact of these environmental factors and their interactions with the individual genetic background in humans is challenging and often requires large cohorts, complicated study designs, and longitudinal set‐ups. In contrast, rodent models offer an ideal system to study the influence of individual environmental aspects under controlled genetic background and standardized conditions. In this review, we highlight findings from studies examining effects of environmental enrichment mimicking stimulation of the brain by its physical and social surroundings as well as of environmental stressors on brain health in the context of Parkinson’s disease. We discuss possible internal molecular transducers of such environmental cues in Parkinson’s disease rodent models and emphasize their potential in developing novel avenues to much‐needed therapies for this still incurable disease.
This article is part of the Special Issue “Synuclein”
The central role of alpha‐synuclein in the etiology of Parkinson’s disease is based on genetics and neuropathology. While familial cases are rare, the preponderance of cases seems sporadic, most likely based on a complex interplay between genetic predispositions, aging processes and environmental influences. In this review, we discuss results from recent studies investigating the impact of environmental enrichment mimicking stimulation of the brain by its physical and social surroundings as well as of environmental stressors using rodent models of Parkinson’s disease.
This article is part of the Special Issue “Synuclein”
Sepsis and septic shock are major causes of mortality during chemotherapy-induced neutropenia for malignancies requiring urgent treatment. Thus, awareness of the presenting characteristics and prompt ...management is most important. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. However, optimal management may differ between neutropenic and non-neutropenic patients. The aim of the current guideline is to give evidence-based recommendations for hematologists, oncologists, and intensive care physicians on how to manage adult patients with neutropenia and sepsis.
Elevated alpha-synuclein (SNCA) gene expression is associated with transcriptional deregulation and increased risk of Parkinson's disease, which may be partially ameliorated by environmental ...enrichment. At the molecular level, there is emerging evidence that excess alpha-synuclein protein (aSyn) impacts the epigenome through direct and/or indirect mechanisms. However, the extents to which the effects of both aSyn and the environment converge at the epigenome and whether epigenetic alterations underpin the preventive effects of environmental factors on transcription remain to be elucidated. Here, we profiled five DNA and histone modifications in the hippocampus of wild-type and transgenic mice overexpressing human SNCA. Mice of each genotype were housed under either standard conditions or in an enriched environment (EE) for 12 months. SNCA overexpression induced hippocampal CpG hydroxymethylation and histone H3K27 acetylation changes that associated with genotype more than environment. Excess aSyn was also associated with genotype- and environment-dependent changes in non-CpG (CpH) DNA methylation and H3K4 methylation. These H3K4 methylation changes included loci where the EE ameliorated the impacts of the transgene as well as loci resistant to the effects of environmental enrichment in transgenic mice. In addition, select H3K4 monomethylation alterations were associated with changes in mRNA expression. Our results suggested an environment-dependent impact of excess aSyn on some functionally relevant parts of the epigenome, and will ultimately enhance our understanding of the molecular etiology of Parkinson's disease and other synucleinopathies.
•SNCA overexpression was associated with altered DNA and histone modifications.•SNCA overexpression and environmental enrichment jointly influenced H3K4 methylation.•Environmental enrichment dampened select H3K4me1 and gene expression changes.
MLL rearrangements play a crucial role in leukemogenesis and comprise a poor prognosis. Therefore, new treatment strategies are urgently needed. We used the CRISPR/Cas9 system to generate an ...innovative leukemia model based on 100% pure MLL-AF4 or -AF9 rearranged cells derived from umbilical cord blood with indefinite growth in cell culture systems. Our model shared phenotypical, morphological and molecular features of patient cells faithfully mimicking the nature of the disease. Thus, it serves as a fundamental basis for pharmacological studies: inhibition of histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is one specific therapeutic approach currently tested in clinical trials. However, success was limited by restricted response warranting further investigation of drug combinations. Recently, it has been shown that the inhibition of protein arginine methyltransferase 5 (PRMT5) exhibits anti-tumoral activity against human cell lines and in MLL mouse models. Here, we used DOT1L and PRMT5 inhibitors in our human MLL-rearranged model demonstrating dose-dependent reduced proliferation, impairment of cell cycle, increasing differentiation, apoptosis, downregulation of target genes and sensitization to chemotherapy. Strikingly, the combination of both compounds led to synergistic anti-tumoral effects. Our study provides a strong rationale for novel targeted combination therapies to improve the outcome of MLL-rearranged leukemias.
MLL rearranged (MLLr) leukemias are associated with a poor prognosis and a limited response to conventional therapies. Moreover, chemotherapies result in severe side effects with significant ...impairment of the immune system. Therefore, the identification of novel treatment strategies is mandatory.
Recently, we developed a human MLLr leukemia model by inducing chromosomal rearrangements in CD34+ cells using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. This MLLr model authentically mimics patient leukemic cells and can be used as a platform for novel treatment strategies. RNA sequencing of our model revealed MYC as one of the most important key drivers to promote oncogenesis. However, in clinical trials the BRD4 inhibitor JQ-1 leading to indirect blocking of the MYC pathway shows only modest activity. We and others previously reported that epigenetic drugs targeting MAT2A or PRMT5 promote cell death in MLLr cells. Therefore, we use these drugs in combination with JQ-1 leading to augmented anti-leukemic effects. Moreover, we found activation of T, NK and iNKT cells, release of immunomodulatory cytokines and downregulation of the PD-1/PD-L1 axis upon inhibitor treatment leading to improved cytotoxicity.
In summary, the inhibition of MYC and MAT2A or PRMT5 drives robust synergistic anti-leukemic activity in MLLr leukemia. Moreover, the immune system is concomitantly activated upon combinatorial inhibitor treatment, hereby further augmenting the therapeutic efficiency.
Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable ...of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, COL4A2, a major component of basement membranes, was found to be upregulated in both A30P aSyn transgenic mice and in dopaminergic neurons expressing A30P aSyn, suggesting a crucial role for collagen related genes in aSyn-induced toxicity. Finally, we observed that A30P aSyn alters Golgi morphology and increases the susceptibility to endoplasmic reticulum (ER) stress in dopaminergic cells. In total, our findings provide novel insight into the putative role of aSyn on transcription and on the molecular mechanisms involved, thereby opening novel avenues for future therapeutic interventions in PD and other synucleinopathies.
•A30P aSyn exhibits robust transcriptional deregulation in transgenic mice.•ER-related pathways are found deregulated in A30P aSyn transgenic mice.•A30P aSyn binds to several regions of DNA and affects exon usage.•A30P aSyn upregulates COL4A2, a major component of basement membranes.•A30P aSyn alters Golgi morphology and increases the susceptibility to ER stress.
Parkinson's disease (PD) is a neurological disorder with complex interindividual etiology that is becoming increasingly prevalent worldwide. Elevated alpha-synuclein levels can increase risk of PD ...and may influence epigenetic regulation of PD pathways. Here, we report genome-wide DNA methylation and hydroxymethylation alterations associated with overexpression of two PD-linked alpha-synuclein variants (wild-type and A30P) in LUHMES cells differentiated to dopaminergic neurons. Alpha-synuclein altered DNA methylation at thousands of CpGs and DNA hydroxymethylation at hundreds of CpGs in both genotypes, primarily in locomotor behavior and glutamate signaling pathway genes. In some cases, epigenetic changes were associated with transcription. SMITE network analysis incorporating H3K4me1 ChIP-seq to score DNA methylation and hydroxymethylation changes across promoters, enhancers, and gene bodies confirmed epigenetic and transcriptional deregulation of glutamate signaling modules in both genotypes. Our results identify distinct and shared impacts of alpha-synuclein variants on the epigenome, and associate alpha-synuclein with the epigenetic etiology of PD.
Cancer patients are at increased risk for central venous catheter-related infections (CRIs). Thus, a comprehensive, practical and evidence-based guideline on CRI in patients with malignancies is ...warranted.
A panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) has developed a guideline on CRI in cancer patients. Literature searches of the PubMed, Medline and Cochrane databases were carried out and consensus discussions were held.
Recommendations on diagnosis, management and prevention of CRI in cancer patients are made, and the strength of the recommendation and the level of evidence are presented.
This guideline is an evidence-based approach to the diagnosis, management and prevention of CRI in cancer patients.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder that affects extensive regions of the nervous system. Its current clinical diagnosis is based on motor symptoms that ...appear late during disease progression when substantial proportions of the nigrostriatal dopaminergic neuron population are lost already. Although disturbances in sleep and other biofunctions often surface years prior to motor impairments and point to a long prodromal phase, these phenotypic signs in a person's midlife lack predictive power. They do, however, signal the unfolding of the disease and suggest molecular correlates that begin deviating early on. Revealing such trajectories, hence, promises not only a better understanding of prodromal PD but may also enable a much-needed earlier diagnosis. A nexus that may harbor such molecular trajectories is the epigenome as key etiological factors of PD-genetics, age, and environment-influence this substrate. An earlier diagnosis would also allow earlier interventions and lifestyle adjustments to improve brain function and reduce symptoms. In this review, we describe the challenges of diagnosing PD early on and highlight the opportunities that may arise from steering research efforts towards comprehensive interrogations of molecular layers during the long-time neglected midlife phase. In particular, we emphasize how existing cohorts of at-risk individuals, available animal models, and suitable markers may come together and aid in revealing molecular trajectories that offer diagnostic utility for PD in its prodromal stage.
Linde and Zimmer-Bensch discuss the role of DNA methylation and its writers, DNA methyltransferases DNMT1 and DNMT3A, in regulating essential genes for GABAergic neuronal functions, as well as genes ...of the endocytosis process critical for synaptic neurotransmission. Besides perturbations in neurons, glia pathology also participates in psychiatric disorders (Cotter et al., 2002). Since DNA methylation is critically implicated in many neuropsychiatric diseases, it presents a potential target for treatment (Sales and Joca, 2016; Shirvani-Farsani et al., 2021). Among all these studies, only the correlation between methylation at the BDNF gene locus and antidepressant effects in MDD was reproduced by multiple groups (Januar et al., 2015; Zhou et al.). Since the antidepressant effect of BDNF is well-established in animal studies (Lee and Kim, 2010), this provides evidence for using current animal models (stress-induced depressive-like behaviors in mice and rats) as valid tools for studying mental disorders. MDD is becoming one of the most severe health problems globally (Otte et al., 2016). Besides chronic stress that is well-accepted as top one risk factor for MDD (Breslau and Davis, 1986), other environmental factors, including dietary influences, contribute to the neuropathogenesis of depression (Firth et al., 2020).
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