A5062844385- Mitochondrial Function and Pathology
- CRISPR and Genetic Engineering
- ATP Synthase and ATPases Research
- Pluripotent Stem Cells Research
- Neurogenesis and neuroplasticity mechanisms
- RNA Research and Splicing
- Neuroscience and Neuropharmacology Research
- 3D Printing in Biomedical Research
- Metabolism and Genetic Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA and protein synthesis mechanisms
- Adipose Tissue and Metabolism
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Blood groups and transfusion
- Single-cell and spatial transcriptomics
- Genomics and Chromatin Dynamics
- Diet and metabolism studies
- Neurological Disease Mechanisms and Treatments
- Multiple Sclerosis Research Studies
- Epigenetics and DNA Methylation
- Cell Image Analysis Techniques
- Neuroscience and Neural Engineering
- Bone Metabolism and Diseases
- Genetic Neurodegenerative Diseases
Heinrich Heine University Düsseldorf
2020-2025
Düsseldorf University Hospital
2020-2025
Max Delbrück Center
2016-2021
Charité - Universitätsmedizin Berlin
2007-2020
German Rheumatism Research Centre
2007
Abstract Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and currently incurable. The lack effective models hampers our understanding the mechanisms underlying neuronal pathology LS. Using patient-derived induced pluripotent stem cells CRISPR/Cas9 engineering, we developed human model LS caused by mutations complex IV assembly gene SURF1 . Single-cell RNA-sequencing multi-omics analysis revealed compromised morphogenesis mutant neural cultures brain...
Abstract Background Patients with mutations in the monocarboxylate transporter 8 (MCT8, SLC16A2 ) suffer from X‐linked recessive Allan‐Herndon‐Dudley syndrome (AHDS), which is characterized by developmental delay and a severe movement disorder. Current trials using thyroid hormone derivatives to overcome defect have failed achieve patient‐oriented therapeutic goals. Objectives Our aim was define type of disorder AHDS an observational cohort study investigate causative role dopaminergic...
Promotion of myelin repair in the context demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also impaired regeneration processes. Hence, relates to replacement lost oligodendrocytes and sheaths-the primary targets attacks. Endogenous remyelination mainly mediated via activation differentiation resident oligodendroglial precursor cells (OPCs), whereas its efficiency...
Spinocerebellar ataxia type-1 (SCA1) is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that somehow linked to neuronal death. However, owing lack of a suitable cellular model, the downstream consequences IIB formation yet be resolved. Here, we describe nuclear aggregation model pathogenic human ataxin-1 characterize effects. Using inducible Sleeping...
The high attrition rate in drug development processes calls for additional human-based model systems. However, the context of brain disorders, sampling live neuronal cells compound testing is not applicable. use human induced pluripotent stem (iPSCs) has revolutionized field disease modeling and discovery. Thanks to iPSC-based differentiation protocols, including tridimensional cerebral organoids, it now possible molecularly dissect pathogenesis a dish. These approaches may allow dissecting...
Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss oligodendrocytes myelin sheaths as it observed multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, its envelope (ENV) protein was previously identified negative regulator OPC...
We generated two pairs of mother–child iPSCs lines for Maternally Inherited Leigh Syndrome (MILS) carrying the m.8993 T > G and m.9176 mutations in MT-ATP6 gene. delivered reprogramming factors OCT4, SOX2, KLF4, c-MYC via Sendai virus. All had a normal karyotype, expressed pluripotency markers, differentiated into three germ layers. Both patient-iPSCs retained same degrees heteroplasmy as their source fibroblasts (>97.0 %). In maternal iPSCs, remained 0.0 % case mutation dropped from 55.0 to...
Abstract Mutations in the mitochondrial complex IV assembly factor SURF1 represent a major cause of Leigh syndrome (LS), rare fatal neurological disorder. -deficient animals have failed to recapitulate neuronal pathology human LS, hindering our understanding disease mechanisms. We generated induced pluripotent stem cells from LS patients carrying homozygous mutations (SURF1 iPS) and performed biallelic correction via CRISPR/Cas9. In contrast corrected cells, iPS showed impaired...
Although new genes can arrive from modes other than duplication, few examples are well characterized. Given high expression in some human brain subregions and a putative link to psychological disorders [e.g., schizophrenia (SCZ)], suggestive of functionality, here we characterize piggyBac transposable element-derived 1 (PGBD1). PGBD1 is nonmonotreme mammal-specific under purifying selection, consistent with functionality. The gene body retains much the original DNA transposon but has...
Excessive ethanol exposure can cause mitochondrial and cellular toxicity. In order to discover potential counteracting interventions, it is essential develop assays capable of capturing the consequences in human neurons, particularly dopaminergic neurons that are crucial for development alcohol use disorders (AUD). Here, we developed a novel high-throughput (HT) assay quantify neuronal toxicity neuron-containing cultures (DNs) from induced pluripotent stem cells (iPSCs). The assay, dubbed...
We present a high-content screening (HCS) protocol for quantifying mitochondrial activity in live neural cells from human induced pluripotent stem (iPSCs). The assessment is based on membrane potential, which influenced by the efficiency of bioenergetics. describe how to perform analysis using both an HCS platform and open-source software CellProfiler. can identify fitness neurons may be used carry out high-throughput compound screenings patient-derived cells. For complete details use...
Background: Patients with mutations in the monocarboxylate transporter 8 (MCT8) suffer from Allan-Herndon-Dudley syndrome (AHDS), characterized by developmental delay and a highly disabling movement disorder. Despite potential of thyroid hormone derivatives to overcome defect, current trials did not achieve patient-oriented therapeutic goals. Objectives: Since most neurological symptoms are related dopaminergic system, we investigated role dopamine its metabolites MCT8 deficiency regard...
The evolution and functional integration of new genes, especially those that become core to key functions, remains enigmatic. We consider the mammal-specific gene, piggyBac transposable element derived 1 (PGBD1), implicated in neuronal disorders. While it no longer recognises transposon-like inverted repeats transposase functionality having been lost, has evolved a role neural homeostasis. Depletion PGBD1 triggers accumulation paraspeckles differentiation. It acts by two modalities, DNA...
Mitochondrial DNA (mtDNA) mutations predominantly cause neurological diseases. Viable neural model systems are lacking due to the challenges of engineering mtDNA, thus hindering search for therapeutic strategies. Here, we demonstrate that progenitor cells (NPCs), directly obtained from human induced pluripotent stem (iPSCs), maintain parental mtDNA profile and exhibit mitochondrial maturation with a metabolic switch away glycolysis. Hence, iPSC-derived NPCs carry correct patient-related...
Abstract Excessive ethanol exposure can cause mitochondrial and cellular toxicity. In order to discover potential counteracting interventions, it is essential develop assays capable of capturing the consequences in human dopaminergic (DA) neurons, which are crucial for development maintenance alcohol use disorders (AUD). Here, we developed a novel high-throughput (HT) assay quantify neuronal toxicity DA neurons from induced pluripotent stem cells (iPSCs). The assay, dubbed m itochondrial n...