Biology subjects

Ohnmacht, J.

Publications and source records attributed to Ohnmacht, J..

9 recordsLinked to original sources

bioRxiv2026

Identification of Parkinson's disease-associated regulatory variants in human dopaminergic neurons reveals modulators of SCARB2 and BAG3 expression

A hallmark of Parkinsons disease (PD) is the degeneration of midbrain dopaminergic neurons (mDANs). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with PD, but causal variants and mechanisms remain unknown. Many PD-associated SNPs reside in regulatory regions, where they may disrupt transcription factor binding sites (TFBS) and alter gene expression. To assess how non-coding PD SNPs affect gene regulation in mDANs, we identify variants predicted to alter TF binding and functionally validate their effects in a cell type-specific context. We integrate time-series transcriptome and chromatin accessibility data from iPSC-derived neurons with chromatin topology and genetic variants. We profile 3D chromatin conformation in neuronal progenitors (smNPCs) and mDANs using LowC, identifying changes in A/B compartments and topologically associated domains. PD SNPs are enriched near genes expressed in mDANs, and we predict 254 regulatory variants that create or disrupt TFBS. Using chromatin conformation data, we link variants to target genes. At the BAG3 and SCARB2 loci, reporter assays in mDANs show reduced transcription driven by PD-associated alleles. Knock-down of NR2C2, a putative SCARB2 regulator, increases SCARB2 expression in differentiating neurons. The PD-associated SCARB2 allele shows reduced chromatin accessibility in mDANs and is associated with decreased expression in brain eQTL data. Insertion of PD-associated BAG3 allele by prime editing reduces chromatin accessibility across cell types, consistent with altered binding of LIM-homeodomain transcription factors. Together, these results prioritize functional PD SNPs and show that variants at SCARB2 and BAG3 modulate gene expression in mDANs, providing mechanistic insight into PD.

molecular biology↗

bioRxiv2025

CBM KG: A Comorbidity-Centric Knowledge Graph Uncovering Causal Pathomechanisms Between COVID-19 and Neurodegenerative Diseases

SummaryCOVID-19 is increasingly recognized as a potential trigger or accelerator of neurodegenerative diseases such as Alzheimers and Parkinsons. To systematically explore the putative molecular and clinical associations between them, we present CBM KG (Causal Biological Mechanisms Knowledge Graph)--a manually curated, comorbidity-centric resource developed within the EU-funded COMMUTE project. CBM KG integrates over 2,800 cause-and-effect or correlative relationships from 63 peer-reviewed publications, highlighting key mechanisms such as viral entry routes, blood-brain barrier alteration, microglial activation, neuroinflammation, and APOE {varepsilon}4-associated susceptibility. Each relationship in the graph is fully traceable to its source evidence, ensuring transparency and reproducibility. Unlike general-purpose or single disease-focused knowledge graphs, CBM KG is specifically designed to represent causal biological mechanisms spanning both infectious and neurodegenerative processes. By encoding directional, cause-and-effect relationships, it supports the interpretation of clinical co-occurrences through plausible mechanistic links between overlapping disease pathways, offering high-resolution insights at both molecular and clinical levels. Availability and implementationThe BEL files, Neo4j database, and Cytoscape visualization files are publicly available at: https://github.com/SCAI-BIO/CBM-Comorbidity-KG.

bioinformatics↗

bioRxiv2025

ZFHX4 is necessary for dopaminergic neuron differentiation and controls cell cycle by regulating LIN28A

The selective degeneration of midbrain dopaminergic neurons (mDANs) is the main pathological hallmark of Parkinsons disease (PD). Although many transcription factors (TFs) guiding mDAN development have been identified, the details of the underlying regulatory networks remain elusive. We have previously generated time-series transcriptomic and epigenomic profiles of human induced pluripotent stem cell (hiPSC)-derived mDANs. Integrative analysis of the data identified ZFHX4 as a prominent super-enhancer-controlled TF induced in mDAN differentiation. ZFHX4 has been associated with neurodevelopmental processes in several species and shows reduced expression in midbrain of PD patients. Using in vitro knockdown (KD) and overexpression experiments, we show that ZFHX4 is necessary but not sufficient for mDAN differentiation. ZFHX4 binds preferentially at active promoter regions and transcriptomic analysis upon ZFHX4 depletion during mDAN differentiation revealed putative primary target genes to be enriched for targets of cell-cycle-related TFs and pathways. Consistently, ZFHX4-depleted cells accumulated in G2-phase of the cell cycle, preventing normal cell cycle progression and exit. The RNA-binding protein LIN28A, involved in stem-cell maintenance and microRNA (miRNA) maturation, emerged as one of the most upregulated genes upon ZFHX4-KD, in parallel with downregulation of neurogenic miRNA miR-9. Moreover, the LIN28A locus was enriched for ZFHX4 binding in CUT&Tag analysis. Taken together, our analysis indicates a pivotal role for ZFHX4 in regulating the cell cycle, specifically in silencing multipotency and proliferative programs, while maintaining mDANs in a post-mitotic state by controlling LIN28A-miR-9 axis.

molecular biology↗

bioRxiv2024

DJ-1 mediates regulation of metabolism and immune response in Parkinsons disease astrocytes and Glioblastoma cells

An inverse correlation for the expression of Parkinsons disease (PD)- and cancer-associated genes has been previously reported. Genes that are upregulated in cancer are frequently downregulated in PD and vice versa. PARK7, encoding DJ-1, was initially identified as an oncogene, but loss of DJ-1 causes early-onset PD. However, it remains elusive how differential DJ-1 levels contribute to opposite cell fates in cancer and PD. Here, we demonstrate specific effects of differential DJ-1 protein levels on the energy metabolism and cell growth in patient-derived cellular models of PD and glioblastoma (GBM) cell lines. Impaired energy metabolism was associated with an increased immune response upon IL-1{beta} stimulation and increased apoptosis and decreased cell growth in models of PD, whereas in GBM cells increased metabolic activity translated into a reduced immune response and increased cell growth. Furthermore, we found decreased glutathione (GSH) synthesis and therefore increased levels of reactive oxygen species (ROS) and oxidized glutathione (GSSG) in models of DJ-1 deficiency and decreased ROS levels in GBM cell lines. Thus, the mechanism by which DJ-1 modulates these phenotypes is the same in both diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/621212v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@4eccb4org.highwire.dtl.DTLVardef@161669corg.highwire.dtl.DTLVardef@197bfc3org.highwire.dtl.DTLVardef@1aecb36_HPS_FORMAT_FIGEXP M_FIG C_FIG DJ-1 levels modulate GSSG/GSH ratio and ROS levels, which results in divergent effects on cell growth and immune response in DJ-1-dependent glial pathologies in glioblastoma and PD. In models of PD, DJ-1 level dependent phenotypes can be rescued by antioxidant treatment that reduces the GSSG/GSH ratio and ROS levels.

neuroscience↗

bioRxiv2024

Park7 deletion leads to age- and sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes

AbstractdispeLoss-of-function mutations in PARK7, encoding for DJ-1, can lead to early onset Parkinsons disease (PD). In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. Interestingly, while at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed specifically in 8-month-old males. The affected genes are involved in processes such as focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of Nuclear factor erythroid 2-related factor 2 (NRF2). Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male, but not female primary astrocytes recapitulated many of the in vivo changes, including downregulation of cytochrome P450 family 1 subfamily B member 1 (CYP1B1), an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in the PARK7 gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes specifically in males through astrocytic alterations in the NRF2-CYP1B1 axis. These findings suggest higher sensitivity of males to loss of DJ-1 and might help to better understand variation in the reported Park7-/-phenotypes.

molecular biology↗

bioRxiv2023

Parkinson's disease-related Miro1 mutation induces mitochondrial dysfunction and loss of dopaminergic neurons in vitro and in vivo

The complex and heterogeneous nature of Parkinsons disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairments as a major driver of neurodegeneration in PD. Recently, the regulator of mitochondrial homeostasis Miro1 has been linked genetically and pathophysiologically to PD. Using 2D and 3D patient-based induced pluripotent stem cells models, including an isogenic control, showed that the Miro1 p.R272Q mutation leads to mitochondrial impairments including increased oxidative stress, disrupted mitochondrial bioenergetics and altered metabolism. This was accompanied by increased -synuclein levels in 2D dopaminergic neurons and by a significant reduction of dopaminergic neurons within midbrain organoids. Knock-in mice expressing mutant p.R285Q Miro1 (orthologue of the human p.R272Q mutation) confirmed the PD-specific dopaminergic neuronal loss in the substantia nigra, accumulation of striatal phosphorylated -synuclein accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.

neuroscience↗

bioRxiv2023

Higher seed yield through selection for reduced seed shattering in Italian ryegrass (Lolium multiflorum Lam.)

Seed shattering, i.e., the loss of seeds at ripening stage shortly before or during seed harvest, is strongly reducing seed yield in Italian ryegrass (Lolium multiflorum Lam.). The aim of this study was to evaluate the possibility to reduce seed shattering within breeding germplasm via recurrent phenotypic selection on spaced plants. Starting from a founder population of 300 plants serving as F0 population, two cycles of phenotypic selection for high and low seed shattering were applied and compared to randomly selected individuals on spaced plant level and in plot trials. Comparison of the five resulting populations in a spaced plant trial revealed a significant effect of selection, with lowest seed shattering (15.3%) observed in the population selected twice for decreased shattering (15.3%) and highest seed shattering (47.9%) for the population selected twice for increased shattering. The same ranking of the five F2 populations was observed in a subsequent trial with sown plots. Thus, using the method presented here, recurrent selection on single spaced plants allows to efficiently reduce seed shattering and, therefore, to increase seed yield in swards.

plant biology↗

bioRxiv2023

Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinsons disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) iPSC reporter line, we have generated time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicted novel central regulators of mDAN differentiation and super-enhancers were used to prioritize key TFs. We find LBX1, NHLH1 and NR2F1/2 to be necessary for mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. NHLH1 is necessary for the induction of neuronal miR-124, while LBX1 regulates cholesterol biosynthesis, possibly through mTOR signaling. Consistently, rapamycin treatment led to an inhibition of mDAN differentiation. Thus, our work reveals novel regulators of human mDAN differentiation.

genomics↗

bioRxiv2020

Single nuclei chromatin profiles of ventral midbrain reveal cell identity transcription factors and cell type-specific gene regulatory variation

Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility such as Parkinsons disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression. We report 20 658 single nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Our dataset provides an extensive resource to study gene regulation in mesencephalon.

genomics↗