A5051485155- Alzheimer's disease research and treatments
- Microtubule and mitosis dynamics
- Protein Structure and Dynamics
- Prion Diseases and Protein Misfolding
- Neuroscience and Neuropharmacology Research
- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- 14-3-3 protein interactions
- Cholinesterase and Neurodegenerative Diseases
- Supramolecular Self-Assembly in Materials
- RNA Research and Splicing
- Enzyme Structure and Function
- Heat shock proteins research
- S100 Proteins and Annexins
- Advanced NMR Techniques and Applications
- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Amino Acid Enzymes and Metabolism
- Computational Drug Discovery Methods
- Advanced Neuroimaging Techniques and Applications
- Wnt/β-catenin signaling in development and cancer
- Nuclear Receptors and Signaling
- Lipid Membrane Structure and Behavior
- Neuroinflammation and Neurodegeneration Mechanisms
- Chemical Synthesis and Analysis
University Hospital Bonn
2024
University of Bonn
2019-2024
German Center for Neurodegenerative Diseases
2014-2023
Center of Advanced European Studies and Research
2013-2022
Max Planck Unit for Structural Molecular Biology
2004-2018
Caesar Systems (United Kingdom)
2016
Max Planck Institute for Metabolism Research
2012-2014
Deutsches Elektronen-Synchrotron DESY
1995-2012
Max Planck Society
2006-2011
Max Planck Institute for Biophysical Chemistry
2007-2010
We have searched for a minimal interaction motif in τ protein that supports the aggregation into Alzheimer-like paired helical filaments. Digestion of repeat domain with different proteases yields GluC-induced fragment comprising 43 residues (termed PHF43), which represents third plus some flanking residues. This self assembles readily thin filaments without appearance, but these are highly competent to nucleate bona fide PHFs from full-length τ. Probing interactions PHF43 overlapping...
The protein Tau aggregates into tangles in the brain of patients with Alzheimer's disease. In solution, however, is intrinsically disordered, highly soluble, and binds to microtubules. It still unclear what initiates conversion from an innocuous phase high solubility functionality solid-like neurotoxic deposits. Here, we show that microtubule-binding repeats Tau, which are lysine-rich, undergo liquid-liquid separation solution. Liquid-liquid demixing causes molecular crowding...
The bis-indole indirubin is an active ingredient of Danggui Longhui Wan, a traditional Chinese medicine recipe used in the treatment chronic diseases such as leukemias. antitumoral properties appear to correlate with their antimitotic effects. Indirubins were recently described potent (IC50: 50–100 nm) inhibitors cyclin-dependent kinases (CDKs). We report here that indirubins are also powerful 5–50 evolutionarily related kinase, glycogen synthase kinase-3β (GSK-3β). Testing series indoles...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDomains of tau Protein and Interactions with MicrotubulesN. Gustke, B. Trinczek, J. Biernat, E.-M. Mandelkow, E. MandelkowCite this: Biochemistry 1994, 33, 32, 9511–9522Publication Date (Print):October 16, 1994Publication History Published online1 May 2002Published inissue 16 October 1994https://pubs.acs.org/doi/10.1021/bi00198a017https://doi.org/10.1021/bi00198a017research-articleACS PublicationsRequest reuse permissionsArticle...
Alzheimer disease is characterized by abnormal protein deposits in the brain, such as extracellular amyloid plaques and intracellular neurofibrillary tangles. The tangles are made of a called tau comprising 441 residues its longest isoform. Tau belongs to class natively unfolded proteins, binds stabilizes microtubules, partially folds into an ordered β-structure during aggregation paired helical filaments (PHFs). Here we show that it possible overcome size limitations have traditionally...
The microtubule-associated protein tau is a natively unfolded in solution, yet it able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer’s disease. In splice isoforms lacking exon 10, this process facilitated by formation β-structure around hexapeptide motif PHF6 (306VQIVYK311) encoded 11. We have investigated structural requirements for PHF polymerization context adult containing four repeats (including 10). addition there exists related PHF6* (275VQIINK280) repeat...
One of the hallmarks Alzheimer's disease is abnormal state microtubule-associated protein tau in neurons. It both highly phosphorylated and aggregated into paired helical filaments, it commonly assumed that hyperphosphorylation causes its detachment from microtubules promotes assembly PHFs. We have studied relationship between phosphorylation by several kinases (MARK, PKA, MAPK, GSK3) The proline-directed MAPK GSK3 are known to phosphorylate most Ser-Pro or Thr-Pro motifs regions flanking...
The microtubule‐associated protein tau is the main component of paired helical filaments (PHFs) Alzheimer's disease, most common senile dementia. To understand origin tau's abnormal assembly we have studied influence other cytosolic components. Here report that PHF strongly enhanced by RNA. RNA‐induced PHFs dependent on formation intermolecular disulfide bridges involving Cys 322 in third repeat tau, and it includes dimerization as an early intermediate. Three‐repeat constructs polymerize...
The Alzheimer-like state of tau protein includes phosphorylation by a proline-directed Ser/Thr kinase present in normal or pathological human brain. Extending earlier results on MAP kinase, we show here that the GSK3, can induce an immune response involving several distinct and phosphorylatable epitopes at Ser-Pro motifs, as well gel mobility shift, similar to kinase. Both kinases behave like microtubule-associated proteins they co-purify through cycles assembly disassembly, both are...
We have shown earlier that certain proline-directed kinases such as MAP kinase or GSK-3 can phosphorylate tau protein in an abnormal manner reminiscent of from Alzheimer paired helical filaments [Drewes et al. (1992); Mandelkow (1992)]. Both are abundant brain tissue and associate physically with microtubules through several cycles assembly disassembly. In this report we show cdk2/cyclin A incorporates = 5 Pi into recombinant tau, it also induces the MR shift antibody reactivity typical tau....
Significance Tau is an important microtubule-associated protein. Although the structure–function relationship of has been intensively studied for many years primarily by molecular biology and biochemical approaches, little still known about mechanisms which interacts with microtubules promotes microtubule assembly. Here, we provide detailed insight into Tau–microtubule association using NMR spectroscopy mass spectrometry. We show that binds to small groups residues, are pathological...
Recent evidence from several laboratories shows that the paired helical filaments of Alzheimer's disease brains consist mainly protein tau in an abnormally phosphorylated form, but mode assembly is not understood. Here we use EM to study constructs derived human brain and expressed Escherichia coli. All or isoforms are rodlike molecules with a high tendency dimerize antiparallel fashion, as shown by antibody labeling chemical crosslinking. The length rods largely determined region internal...
We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression four-repeat domain human carrying FTDP17 (frontotemporal dementia and parkinsonism linked chromosome 17) mutation ΔK280 (Tau RD /ΔK280), or plus proline mutations in hexapeptide motifs /ΔK280/I277P/I308P). The accelerates aggregation (“proaggregation mutant”), whereas inhibit vitro cell models (“antiaggregation mutant”)....
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, a common extended haplotype spanning across MAPT locus is associated with increased risk of PSP Parkinson's disease.We identified rare variant (p.A152T) patient clinical diagnosis assessed its frequency multiple independent series patients neurodegenerative conditions...
Abstract Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound are directly connected the amino acid content disordered protein regions. Lysine plays an important role in cellular function, but little is known about its condensation. Here we show that disorder abundant protein/RNA granules lysine enriched regions proteins P-bodies compared entire human proteome. Lysine-rich polypeptides phase separate into...
Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 full-length tau, which allow the quantification 3-repeat (3R) 4-repeat (4R) tau isoforms. Plasma EV levels 3R/4R ratios were determined a cohort 704 patients, including 37 genetically 31 neuropathologically proven cases. Diagnostic groups comprised...