A5069267269- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- DNA Repair Mechanisms
- Pharmacogenetics and Drug Metabolism
- Parkinson's Disease Mechanisms and Treatments
- Connexins and lens biology
- Drug Transport and Resistance Mechanisms
- Glioma Diagnosis and Treatment
- Neuroscience and Neuropharmacology Research
- RNA Research and Splicing
- PARP inhibition in cancer therapy
- Cell death mechanisms and regulation
- Ion channel regulation and function
- Nuclear Receptors and Signaling
- Pain Mechanisms and Treatments
- Analytical Chemistry and Chromatography
- Trace Elements in Health
- Endoplasmic Reticulum Stress and Disease
- Botanical Research and Chemistry
- Nuclear Structure and Function
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Heat shock proteins research
University of Bonn
2008-2024
University Hospital Bonn
2005-2024
German Center for Neurodegenerative Diseases
2021
KU Leuven
2005-2006
University of Groningen
2003
Ontwikkelingsmaatschappij Oost Nederland
2003
May Institute
2002
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
2001
University of Tübingen
1999
Robert Bosch (Germany)
1994-1997
Many neurodegenerative diseases are caused by intracellular, aggregate-prone proteins, including polyglutamine-expanded huntingtin in Huntington's disease (HD) and mutant tau fronto-temporal dementia/tauopathy. Previously, we showed that rapamycin, an autophagy inducer, enhances fragment clearance attenuated toxicity. Here show much wider applications for this approach. Rapamycin the autophagic of different proteins with long polyglutamines a polyalanine-expanded protein, reduces their also...
Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate peroxisome proliferator-activated receptor-γ (PPARγ), which is a nuclear transcriptional regulator. Here we show PPARγ depletion potentiates β-secretase [β-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARγ, as well and activators,...
Variable expression and function of the cytochrome P4502D6 (CYP2D6) leads to distinct phenotypes termed ultrarapid (UM), extensive (EM), intermediate (IM) poor metabolizer (PM). Whereas PM phenotype is known be caused by two null-alleles leading absence functional CYP2D6 protein, large variability among individuals with alleles remained largely unexplained. In this study, we systematically investigated 76 liver biopsies from sparteine metabolic ratios (MRS) for relationships between...
Mutations in the valosin-containing protein (VCP) gene on chromosome 9p13-p12 recently have been shown to cause autosomal dominant inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. Here, we report central nervous system autopsy findings a 55-year-old German patient dementia who harbors heterozygous R155C missense mutation residing N-terminal CDC48 domain VCP, which is involved ubiquitin binding. We demonstrate that mutant VCP causes novel type...
Mutations in the valosin-containing protein (VCP, p97) gene on chromosome 9p13-p12 cause a late-onset form of autosomal dominant inclusion body myopathy associated with Paget disease bone and frontotemporal dementia (IBMPFD). We report pathological consequences three heterozygous VCP (R93C, R155H, R155C) mutations human striated muscle. IBMPFD skeletal muscle pathology is characterized by degenerative changes filamentous VCP- ubiquitin-positive cytoplasmic nuclear aggregates. Furthermore,...
Ataxin-3 (AT3), the disease protein in spinocerebellar ataxia type 3 (SCA3), has been associated with ubiquitin–proteasome system and transcriptional regulation. Here we report that normal AT3 binds to target DNA sequences specific chromatin regions of matrix metalloproteinase-2 (MMP-2) gene promoter represses transcription by recruitment histone deacetylase (HDAC3), nuclear receptor corepressor (NCoR), deacetylation histones bound promoter. Both expanded physiologically interacted HDAC3...
There is increasing evidence that dendritic cell (DC) immunogenicity not only positively regulated by ligands of pattern recognition receptors, but also negatively signals prevent DC activation and full functional maturation. Depending on their status, DCs can induce either immunity or tolerance. In this study, we provide molecular the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) a negative regulator maturation function. Sustained PPARgamma in murine...
The nuclear presence of the expanded disease proteins is critical importance for pathogeneses polyglutamine diseases. Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls localization, aggregation and stability ataxin-3 (ATXN3), in spinocerebellar ataxia type 3 (SCA3). Serine 340 352 within third ubiquitin-interacting motif ATXN3 were particularly important localization normal mutation these sites robustly reduced formation inclusions; a putative leader sequence...
Ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3), binds to target gene promoters and modulates transcription by interaction with transcriptional regulators. Here, we show that ATXN3 interacts forkhead box O (FOXO) factor FOXO4 activates FOXO4-dependent of manganese superoxide dismutase (SOD2) gene. Upon oxidative stress, translocate nucleus, concomitantly bind SOD2 promoter increase expression antioxidant enzyme SOD2. Compared normal ATXN3, mutant has a reduced...
Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by CAG repeat expansion in the coding region of gene encoding ataxin-3. To study putative alterations expression induced expanded ataxin-3, we performed PCR-based cDNA subtractive hybridization cell culture model SCA3. In rat mesencephalic CSM14.1 cells stably expressing found significant upregulation mRNAs endopeptidase matrix metalloproteinase 2 (MMP-2), transmembrane protein amyloid precursor protein, interleukin-1...
The clock gene ARNTL is associated with the transcription activation of monoamine oxidase A according to previous literature. Thus, we hypothesised that methylation may differ between bipolar disorder (BD) and controls.The status one CpG island covering first exon (PS2) site in 5' region (cg05733463) were analysed patients BD (n = 151) versus controls 66). Methylation analysis was performed by bisulphite-conversion DNA from fasting blood EpiTect Bisulfite Kit, PCR pyrosequencing. Analysis...
Glioblastoma cells assemble to a syncytial communicating network based on tumor microtubes (TMs) as ultra-long membrane protrusions. The relationship between architecture and transcriptional profile remains poorly investigated. Drugs that interfere with this connectivity such meclofenamate (MFA) may be highly attractive for glioblastoma therapy.
Tight regulation of the balance between self-renewal and differentiation neural stem cells is crucial to assure proper development. In this context, Notch signaling a well-known promoter stemness. contrast, bifunctional brain-enriched microRNA miR-9/9∗ has been implicated in promoting neuronal differentiation. Therefore, we set out explore role both regulators human cells. We found that decreases activity by targeting NOTCH2 HES1, resulting an enhanced Vice versa, expression levels depend on...
Glioblastoma is the most common and aggressive primary tumor of central nervous system with poor outcome. Current gold standard treatment surgical resection followed by a combination radio- chemotherapy. Efficacy temozolomide (TMZ), chemotherapeutic agent, depends on DNA methylation status O6-methylguanine methyltransferase (MGMT), which has been identified as prognostic biomarker in glioblastoma patients. Clinical studies revealed that patients hypermethylated MGMT promoter have better...
The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or ataxia 3 (SCA3) is the most common autosomal dominant form, caused by expansion CAG repeats within ataxin-3 (ATXN3) gene. This mutation results in expression an abnormal protein containing long polyglutamine (polyQ) stretches that confers toxic gain function and leads to misfolding aggregation ATXN3 neurons. As result process, SCA3 patients are severely disabled die...
Spinocerebellar ataxia type 3 (SCA3) is caused by a CAG/polyglutamine repeat expansion in the SCA3 gene. To analyse pathogenic mechanisms SCA3, we have generated ataxin-3-expressing rat mesencephalic CSM14.1 cells. In these cells, post-mitotic neuronal phenotype induced temperature shift. The isolated stable cell lines provided high level expression of non-expanded (Q23) or expanded (Q70) human full-length ataxin-3. cells expressing ataxin-3 developed nuclear inclusion bodies, strong...
Spinocerebellar ataxia type 3 (SCA3) is a late-onset neurodegenerative disorder caused by the expansion of polyglutamine tract within gene product, ataxin-3. We have previously shown that mutant ataxin-3 causes upregulation inflammatory genes in transgenic SCA3 cell lines and human pontine neurons. report here complex pattern transcriptional changes microarray expression profiling Northern blot analysis model. Twenty-three differentially expressed involved reactions, nuclear transcription,...