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Neuroprotective role of high dose Vitamin D supplementation in multiple sclerosis: sub-analysis of the EVIDIMS trial
No full textBACKGROUND: Previous evidence suggests that vitamin D may help with neurodegeneration in multiple sclerosis (MS). Considering this, the study aims to investigate whether higher-dose vitamin D supplementation in individuals with MS can lead to reduced atrophy, as measured by optical coherence tomography (OCT) and MRI structural outcomes. This objective builds upon the established notion of thalamic and brainstem atrophy as reliable markers of disease progression and the potential association between adequate vitamin D levels and improved visual outcomes in MS patients. OBJECTIVE: To assess the impact of vitamin D as a neuroprotective intervention on visual and imaging biomarkers. METHODS: Participants enrolled in the EVIDIMS trial underwent an assessment to investigate the impact of high and low-dose vitamin D supplementation at 12 and 18 months using a nonparametric multiple contrast test procedure (MCTP). The primary outcomes included four MRI-radiological measures: change in the mean upper cervical cord area (MUCCA) and hippocampal, thalamic and brainstem volumes, and the visual system outcomes included assessment of the peripapillary retinal nerve fiber layer (pRNFL) thickness and macular combined ganglion cell and inner plexiform layer (GCIPL), and inner nuclear layer (INL). RESULTS: MCTPs indicated that there were no statistically significant differences in the volumes of the thalamus, hippocampus, and brainstem, as well as in MUCCA, between the low and high-dose supplementation groups. Moreover, MTCPs only revealed a different thinning pattern in the INL at 18 months between the low versus high-dose treatment arm attributable to patients who suffered optic neuritis (NO), with no significant differences in neither pRNFL nor GCIPL. CONCLUSION: Vitamin D supplementation did not affect MS imaging parameters. However, future studies should thoroughly evaluate patient histories of attacks and endogenous vitamin D levels before inclusion in dose-related investigations
Structures of EHD2 filaments on curved membranes provide a model for caveolar neck stabilization
Get PDFCaveolae are flask-shaped invaginations of the plasma membrane serving critical functions in mechano-protection and signal transduction. Caveolar dynamics, such as movement within the plasma membrane or endocytosis, relies on precise shaping of the highly curved caveolar necks. The dynamin-like EHD2 ATPase is proposed to form an oligomeric scaffold around the caveolar neck, but its detailed molecular action is poorly understood. Here, we employed cryo-electron tomography to elucidate structures of EHD2 filaments oligomerized on tubulated liposomes. EHD2 filaments form a highly curved membrane scaffold which stabilizes a sophisticated tubular membrane geometry with undulations along the tube’s axis. An amino-terminal sequence facilitates this geometry by inserting into the membrane, thereby acting as a spacer between adjacent filaments. Moreover, in endothelial cells lacking EHD2, caveolar necks become narrower and elongated. Our structural work provides the molecular framework for understanding EHD2 scaffold formation and its cellular function in caveolar dynamics
Chemical targeting of the ATXN1 aa99–163 interaction site suppresses polyQ-expanded protein dimerization
Get PDFSpinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in the ATXN1 protein. This expansion is thought to be responsible for the gradual aggregation of the mutant protein, which is associated with increased cytotoxicity and neuronal cell death. Apart from the polyQ tract, other domains in ATXN1 are also involved in the initial events of protein aggregation, such as a dimerization domain that promotes protein oligomerization. ATXN1 interacts with various proteins; among them, MED15 significantly enhances the aggregation of the polyQ-expanded protein. Therefore, we set to identify the interaction site between ATXN1 and MED15 and assess whether its chemical targeting would affect polyQ protein aggregation. First, we predicted the structures of ATXN1 and MED15 and simulated their interaction. We experimentally validated that amino acids (aa) 99–163 of ATXN1 and aa548–665 of MED15 are critical for this protein–protein interaction (PPI). We also showed that the aa99–163 domain in ATXN1 is involved in the dimerization of the mutant isoform. Targeting this domain with a chemical compound identified through virtual screening (Chembridge ID: 5755483) inhibited both the interaction of ATXN1 with MED15 and the dimerization of polyQ-expanded ATXN1. These results strengthen our assumption that the aa99–163 domain of ATXN1 may be involved in polyQ protein aggregation and highlight compound 5755483 as a potent first-in-class therapeutic agent for SCA1
High-throughput single-cell CRISPRi screens stratify neurodevelopmental functions of schizophrenia-associated genes
Get PDFSchizophrenia is a complex neuropsychiatric disorder with strong genetic underpinnings, yet the molecular mechanisms linking genetic risk to disrupted brain development remain poorly understood. Transcription factors (TFs) and chromatin regulators (CRs) are increasingly implicated in neuropsychiatric disorders, where their dysregulation may disrupt neurodevelopmental programs. Despite this, systematic functional interrogation in human models has been limited. Here, we combine pooled CRISPR interference (CRISPRi) screens with high-throughput single-cell multiomic profiling in hiPSC-derived neural progenitors and neurons to functionally assess 65 schizophrenia-associated genes. Based on public datasets and literature review, we selected 55 TFs and CRs, along with ten additional risk genes whose loss-of-function has been linked to schizophrenia. Our single-cell CRISPRi readouts revealed that perturbations in TFs and CRs converge on disrupting neurodevelopmental timing. CRISPRi of several factors delayed neural differentiation, whereas others, such as the knockdown of MCRS1, drove precocious neural commitment. Validation screens combined with cell cycle and metabolic indicators confirmed the differentiation-restricting or -promoting roles of these TFs and CRs. Multimodal trajectory analysis uncovered discrete transcriptional and epigenomic states representing delayed and accelerated neurodevelopment, enriched for schizophrenia GWAS loci and disease-relevant pathways. Gene regulatory network (GRN) inference identified TCF4 and ZEB1 as critical mediators opposing the neural differentiation trajectory. Functional overexpression of these TFs followed by chromatin profiling demonstrated that TCF4 restrains, while ZEB1 promotes, neural differentiation in a stage-specific and competitive manner. Furthermore, we show that MCRS1 represses ZEB1 expression, positioning MCRS1 as a key brake on premature neurodevelopment. Together, our study establishes a scalable framework that integrates genetic perturbation, single-cell multiomics, and GRN modeling to functionally annotate disease-linked genes. We reveal convergent regulatory axes that underlie altered neurodevelopmental timing in schizophrenia, offering mechanistic insights into how chromatin misregulation contributes to disease pathogenesis
Factor-H-related protein 1 (FHR1), a promotor of para-inflammation in age-related macular degeneration
Get PDFAge-related macular degeneration (AMD), a multifactorial type of retinal degeneration represents the most common cause for blindness in elderly. Polymorphisms in complement factor-H increase, while absence of factor-H-related protein-1 (FHR1) decreases the AMD risk, currently explained by their opposing relationship. Here we identify a FHR1-driven pathway fostering chronic cellular inflammation. FHR1 accumulates below the retinal pigment epithelium (RPE) in AMD donor tissue and similarly the murine homolog, muFHR1 is abundant in three AMD-relevant mouse models. These mouse models express the muFHR1 receptor EGF-like module-containing mucin-like hormone receptor 1 (Emr1) on the RPE and on invading mononuclear phagocytes (MP), where both cells form clusters via muFHR1/Emr1. FHR1 ignited EMR2-dependent Ca(2+)-signals and gene expression in both human RPE cell line and in vivo where muFHR1 affects Emr1(+) cells (RPE and MP) gene expression shown by RNAseq analysis. As muFHR1 deletion in mice revealed significantly reduced MP invasion and neoangiogenesis in laser-induced choroidal neovascularization, we hypothesize that FHR1 accumulates, stabilizes and activates MP in the stage of RPE degeneration
Lesion-network mapping of poststroke depressive symptoms: evidence from two prospective ischemic stroke cohorts
No full textBACKGROUND: Poststroke depression affects up to one-third of stroke survivors, significantly impacting recovery and quality of life. However, its pathophysiology remains unclear. METHODS: We analyzed 2 independent, prospective ischemic stroke cohorts (PROSCIS-B [Prospective Cohort of Incident Stroke Berlin] and BAPTISe [Biomarkers and Perfusion-Training-Induced Changes After Stroke]; n=377) enrolled at the Charité Hospital, Germany, to identify brain regions and networks associated with depressive symptoms poststroke. Lesion-symptom mapping assessed associations between lesion location and depressive symptoms measured by the Center for Epidemiological Studies Depression Scale at 6 (BAPTISe) or 12 (PROSCIS-B) months poststroke. Lesion-network mapping evaluated lesion connectivity with brain networks. A mixed-effects model, including cohort as a random effect, assessed the relationship between network similarity (Pearson correlation) and Center for Epidemiological Studies Depression Scale scores. Dice coefficients (DC) quantified spatial overlap with canonical resting-state networks. RESULTS: Lesion-symptom mapping showed no significant associations between lesion location and depressive symptoms. In contrast, lesion-network mapping revealed that lesion connectivity to brain regions including the frontal pole, middle and inferior frontal gyri, inferior temporal gyrus, supramarginal gyrus, angular gyrus, frontal orbital cortex, and thalamus weakly correlated with Center for Epidemiological Studies Depression Scale scores (β, 11.4 [95%CI, 1.8–21.1]; P=0.02). These regions overlapped with the frontoparietal (DC=0.28), salience (DC=0.27), and default mode (DC=0.20) networks, as well as a published depression circuit (DC=0.43). However, these findings did not replicate across data sets. CONCLUSIONS: Lesion location alone was not associated with poststroke depression. However, connectivity-based analyses implicated disruption of large-scale brain networks in the development of depressive symptoms. The failure to validate this association across data sets underscores the need for further studies with more comparable patient populations—particularly in terms of stroke severity and harmonized assessment time-points—to confirm these findings and their clinical relevance. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01954797
Maternal smoking in early pregnancy disrupts placental function through syncytiotrophoblast and macrophage dysregulation
Get PDFSmoking in pregnancy is the leading avoidable cause of gestational morbidity and mortality, causally linked to fetal growth restriction (FGR). The placenta, functional interface between mother and fetus is essential for healthy fetal development. For the first time, we studied cell type-resolved smoking effects on placental development at high molecular resolution using single-nucleus RNA sequencing and deep visual proteomics of matched tissues. We validated our findings through an independent cohort and in-vitro cigarette smoke exposure to primary human trophoblast cells. Our results show placental macrophages (Hofbauer cells; HBC) and the syncytiotrophoblast (STB) barrier are most affected by smoking, with dysregulation of cell-cell adhesion, extracellular matrix organization, and stress phenotype. STBs show moderate compositional increases in smokers and in-silico trophoblast differentiation modelling indicates a preferential shift towards the STB lineage in this group. The trophoblast displays a large upregulation of pro-angiogenic effectors, increases in xenobiotic detoxification, reduced mitochondrial function, and vastly altered transmembrane transport. These molecular changes affect placental development with important consequences for fetal growth. We provide insight into placental dysfunction contributing to FGR early in pregnancy, before clinical symptoms appear. We anticipate this data to advance diagnostics and therapies to improve FGR outcomes
Imidazole propionate is a driver and therapeutic target in atherosclerosis
Get PDFAtherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors1. However, individuals at risk for early vascular disease often remain unidentified2. Recent research has identified new molecules in the pathophysiology of atherosclerosis3, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy. Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation. Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP–I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP–I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis
At the crossroads of infection and malignancy: the challenge of tuberculosis in migrating populations - case report and epidemiologic analysis
Get PDFINTRODUCTION: Mycobacterium tuberculosis infection might result in fatal outcome in patients with haematologic malignancies or those with primary or iatrogenic immunodefects. However, in countries with low tuberculosis (TB) incidence the awareness for TB is still challenging, with an increasing need due to migrating populations from regions with high TB to low TB incidence countries. CASE REPORT AND EPIDEMIOLOGICAL ANALYSIS: A 52-year-old caucasian female, refugee from Afghanistan, presented at University Hospital Charité (Berlin, Germany) with progressive left-sided hearing loss due to ear canal obstruction as well as right axillary exophytic and ulcerating skin lesions, finally diagnosed as BRAF-V600E-mutated Langerhans cell histiocytosis (LCH). Following systemic chemotherapy, LCH showed complete remission (CR) with however unexpectedly progressive left-axillary lymphadenopathy. Biopsy of these lymph nodes revealed granulomatous inflammation with central caseous necroses. Mycobacterium tuberculosis DNA was undetectable in a biopsy from the lesion, but culture of fresh re-biopsy material showed growth of M. tuberculosis. Given the patient´s migration history from a high-prevalence (Afghanistan) to a low-prevalence (Germany) TB country, we also present the long-time trend of the total number of TB patients notified in Germany in 2002–2023, i.e. a total of 21 years, aggregated by country of birth. Whereas the number of TB patients born in Germany is decreasing since 2002, the number of patients born abroad exceeded the number of those born in Germany in 2012, and remained higher ever since. CONCLUSION: Our report highlights the challenge to treat patients at the crossroads of malignancy and TB, and the need for appropriate attention and awareness of physicians of the increased TB risk in people migrating from a high- to a low-burden TB country. Also, the case demonstrates once more the high value of culture for diagnosis of mycobacteria infection. CLINICAL TRIAL: Not applicable