A5050034567- Alzheimer's disease research and treatments
- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Parkinson's Disease Mechanisms and Treatments
- Trace Elements in Health
- Advanced Fluorescence Microscopy Techniques
- Protein Structure and Dynamics
- Tea Polyphenols and Effects
- Supramolecular Self-Assembly in Materials
- Cell Image Analysis Techniques
- Ginkgo biloba and Cashew Applications
- Cholinesterase and Neurodegenerative Diseases
- Nanoparticle-Based Drug Delivery
- Biotin and Related Studies
- Lipid Membrane Structure and Behavior
- Skin and Cellular Biology Research
- Computational Drug Discovery Methods
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Lipid metabolism and biosynthesis
- Tryptophan and brain disorders
- Cellular transport and secretion
- Ubiquitin and proteasome pathways
- Botulinum Toxin and Related Neurological Disorders
- Biochemical and biochemical processes
- Lysosomal Storage Disorders Research
MRC Prion Unit
2018-2025
University College London
2018-2025
Medical Research Council
2019-2023
Washington University in St. Louis
2011-2021
Max Delbrück Center
2008-2020
Ningbo University
2011
Scripps Research Institute
2004-2009
Ludwig-Maximilians-Universität München
2004-2005
Robert Koch Institute
2004
Max Planck Institute for Biophysical Chemistry
1997-2000
Protein misfolding and formation of β-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity decay in various human disorders including Alzheimer’s Parkinson’s disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits α-synuclein amyloid-β fibrillogenesis. It associates with natively unfolded polypeptides promotes self-assembly unstructured oligomers a new type. Whether EGCG disassembles preformed fibrils, however, remained...
Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer's disease, which associated with the misassembly Aβ 1-42 peptide. Aggregation-mediated toxicity was reduced in Caenorhabiditis elegans when aging slowed by decreased insulin/insulin growth factor–1–like signaling (IIS). The downstream transcription factors, heat shock factor 1, and DAF-16 regulate opposing disaggregation activities to promote cellular survival response constitutive...
The accumulation of amyloid-beta (Aβ) and tau aggregates is a pathological hallmark Alzheimer's disease. Both polypeptides form fibrillar deposits, but several lines evidence indicate that Aβ toxic oligomeric aggregation intermediates. Depleting such structures could thus be powerful therapeutic strategy. We generated fragment (His-K18ΔK280) forms stable, toxic, in vitro. show (-)-epigallocatechin gallate (EGCG), green tea polyphenol was previously found to reduce aggregation, inhibits the...
A definite diagnosis of prion diseases such as Creutzfeldt–Jakob disease (CJD) relies on the detection pathological protein (PrP Sc ). However, no test for PrP in cerebrospinal fluid (CSF) has been available thus far. Based a setup confocal dual-color fluorescence correlation spectroscopy, technique suitable single molecule detection, we developed highly sensitive method . Pathological aggregates were labeled by specific antibody probes tagged with fluorescent dyes, resulting intensely...
Protein folding barriers result from a combination of factors including unavoidable energetic frustration nonnative interactions, natural variation and selection the amino acid sequence for function, and/or pressure against aggregation. The rate-limiting step human Pin1 WW domain is formation loop 1 substructure. native conformation this six-residue positions side chains that are important mediating protein–protein interactions through binding Pro-rich sequences. Replacement wild-type...
Anfinsen showed that a protein's fold is specified by its sequence. Although it clear why mutant proteins form amyloid, harder to rationalize wild-type protein adopts native conformation in most individuals, but misfolds minority of others, what should be common extracellular environment. This discrepancy suggests another event likely triggers misfolding sporadic amyloid disease. One possibility an abnormal metabolite, generated only some covalently modifies the or peptide and causes...
4-Hydroxynonenal (4-HNE), formed as a consequence of oxidative stress, exists at increased concentrations in Alzheimer's disease (AD) patients and is found amyloid β peptide (Aβ) plaques associated with AD. Although it remains an open question to whether stress causative factor or AD, we show here that 4-HNE, putatively resulting from the peroxidation lipids, covalently modifies Aβ, triggering its aggregation. These Aβ modifications result 1,4 conjugate addition and/or Schiff base formation,...
Causal therapeutic approaches for amyloid diseases such as Alzheimer's and Parkinson's disease targeting toxic oligomers or fibrils are still emerging. Here, we show that theaflavins (TF1, TF2a, TF2b, TF3), the main polyphenolic components found in fermented black tea, potent inhibitors of amyloid-β (Aβ) α-synuclein (αS) fibrillogenesis. Their mechanism action was compared to two established formation, (-)-epigallocatechin gallate (EGCG) congo red (CR). All three compounds reduce...
The accumulation of amyloid β peptide(1–42) (Aβ(1–42)) in extracellular plaques is one the pathological hallmarks Alzheimer disease (AD). Several studies have suggested that cellular reuptake Aβ(1–42) may be a crucial step its cytotoxicity, but uptake mechanism not yet understood. Aβ present an aggregated form prior to uptake. Alternatively, monomeric peptide enter endocytic pathway and conditions compartments induce aggregation process. Our study aims answer question whether aggregate...
Inherited prion diseases (IPD) secondary to mutations of the protein gene, PRNP, exhibit diverse clinical phenotypes, capable mimicking numerous primary neurodegenerative conditions. We describe phenotype and neuropathological findings in a family from County Limerick Ireland presenting with Alzheimer's disease-like cognitive decline motor symptoms caused by novel missense mutation PRNP. This occurs PRNP central lysine cluster (CLC; codon 101-110), resulting substitution threonine isoleucine...
Dual-color fluorescence cross-correlation spectroscopy (dual-color FCS) has previously been shown to be a suitable tool not only for binding but also catalytic rate studies. In this work, its application as rapid method high-throughput screening (HTS) and evolutionary biotechnology is described. This called RAPID FCS (rapid assay processing by integration of dual-color does depend on the characterization diffusion parameters that prerequisite conventional correlation spectroscopy. were...
The process of amyloid formation by the β peptide (Aβ), i.e., misassembly Aβ peptides into soluble quaternary structures and, ultimately, fibrils, appears to be at center Alzheimer's disease (AD) pathology. We have shown that abnormal oxidative metabolites, including cholesterol-derived aldehydes, modify and accelerate early stages amyloidogenesis (the spherical aggregates). This process, which we termed metabolite-initiated protein misfolding, could explain why hypercholesterolemia...
Prions are thought to replicate in an autocatalytic process that converts cellular prion protein (PrP C ) the disease-associated misfolded PrP isoform Sc ). Our study scrutinizes this hypothesis by vitro misfolding cyclic amplification (PMCA). In serial transmission PMCA experiments, was inoculated into healthy hamster brain homogenate containing . Misfolded amplified rounds of sonication and incubation reinoculated fresh every 10 rounds. The depended on substrate could be inhibited...
The structures of oligomeric intermediate states in the aggregation process Alzheimer's disease β-amyloid peptides have been subject debate for many years. Bacterial inclusion bodies contain large amounts small heat shock proteins (sHSPs), which are highly homologous to those found plaques brains patients. sHSPs break down amyloid fibril structure vitro and induce assemblies. Prokaryotic protein overexpression thus mimics conditions encountered cell under stress allows Aβ be investigated...
Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem (MSP) associated with dominant mutations Valosin Containing Protein (VCP). MSP patients have muscle neuronal degeneration characterized by aggregate pathology that can include αS, Tau TDP-43. Methods We performed a fluorescent...
Abstract Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers remarkably useful in the phase, but their potential to predict onset healthy people remains unclear. This is relevant not only design of preventive strategies those at-risk diseases, more broadly, because prion-like mechanisms thought underpin many neurodegenerative disorders. Here, we report accrual a...