A5056814808- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Advanced Chemical Physics Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- Photochemistry and Electron Transfer Studies
- Spectroscopy and Quantum Chemical Studies
- Cholinesterase and Neurodegenerative Diseases
- Quantum, superfluid, helium dynamics
- Prion Diseases and Protein Misfolding
- GaN-based semiconductor devices and materials
- Advanced Fluorescence Microscopy Techniques
- Molecular Spectroscopy and Structure
- Tryptophan and brain disorders
- Spectroscopy and Laser Applications
- Crystallography and molecular interactions
- Dementia and Cognitive Impairment Research
- Protein Structure and Dynamics
- Analytical Chemistry and Sensors
- Neurological disorders and treatments
- Neuroscience and Neuropharmacology Research
- Mitochondrial Function and Pathology
- S100 Proteins and Annexins
- ZnO doping and properties
- Genetic Neurodegenerative Diseases
- Lipid Membrane Structure and Behavior
University of Sheffield
2020-2025
Government Medical College
2025
CT Group Of Institutions
2022-2023
Systems, Applications & Products in Data Processing (United Kingdom)
2023
University of Cambridge
2017-2022
UK Dementia Research Institute
2020-2022
AstraZeneca (United Kingdom)
2021
ORCID
2021
Indian Institute of Technology Bombay
2011-2020
University of Tübingen
2016-2020
Abstract Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer’s disease. Here, we find soluble aggregates formed at different stages amyloid beta (Aβ42) induce disruption lipid bilayers and an inflammatory response extents. Further, by using gradient ultracentrifugation assay, show smaller those most potent inducing membrane permeability effectively...
Abstract Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the drives ferroptosis depends on conformational structure aggregate, as well oxidation state membrane. We generated human stem cell-derived models synucleinopathy, characterized by intracellular formation α-synuclein aggregates bind...
Abstract Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked intracellular conformational states α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, show here that converts from monomeric state into two distinct oligomeric in neurons concentration-dependent sequence-specific manner. Three-dimensional...
Which isoforms of apolipoprotein E (apoE) we inherit determine our risk developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, relevance direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all associate with Aβ in early stages aggregation then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% mass diffusible aggregates detected frontal...
As a key player of the protein quality control network cell, molecular chaperone Hsp70 inhibits aggregation amyloid tau. To date, mechanism this inhibition and tau species targeted by remain unknown. This is partly due to inherent difficulty studying aggregates because their heterogeneous transient nature. Here, we used ensemble single-molecule fluorescence measurements dissect how counteracts self-assembly process K18 ΔK280 variant. We found that blocks early stages suppressing formation...
Proteins fold into a single structural ensemble but can also misfold many diverse structures including small aggregates and fibrils, which differ in their toxicity. The aggregate surface properties play an important role how they interact with the plasma membrane cellular organelles, potentially inducing toxicity, however, these have not been measured to date due lack of suitable methods. Here, we used spectrally resolved, super-resolution imaging method combined environmentally sensitive...
Soluble aggregates of amyloid-β (Aβ) have been associated with neuronal and synaptic loss in Alzheimer's disease (AD). However, despite significant recent progress, the mechanisms by which these aggregated species contribute to progression are not fully determined. As analysis human cerebrospinal fluid (CSF) provides an accessible window into molecular changes progression, we characterised soluble present CSF samples from individuals AD, mild cognitive impairment (MCI) healthy controls using...
Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in development tauopathies. We found that sequential hyperphosphorylation by kinase A conjugation with either glycogen synthase 3β or stress activated 4 enabled recombinant wild-type isoform 0N4R spontaneously polymerize into small amorphous vitro. employed tandem mass spectrometry determine phosphorylation sites, high-resolution native measure degree...
Extensively studied Mn-doped semiconductor nanocrystals have invariably exhibited photoluminescence over a narrow energy window of width $\ensuremath{\le}150\text{ }\text{ }\mathrm{meV}$ in the orange-red region and surprisingly large spectral ($\ensuremath{\ge}180\text{ }\mathrm{meV}$), contrary to its presumed atomic-like origin. Carrying out emission measurements on individual single supported by ab initio calculations, we show that Mn PL emission, fact, can (i) vary much wider range...
Abstract To quantify and characterize the potentially toxic protein aggregates associated with neurodegenerative diseases, a high‐throughput assay based on measuring extent of aggregate‐induced Ca 2+ entry into individual lipid vesicles has been developed. This approach was implemented by tethering containing sensitive fluorescent dye to passivated surface changes in fluorescence as result membrane disruption using total internal reflection microscopy. Picomolar concentrations Aβ42 oligomers...
The aberrant aggregation of α-synuclein is associated with several human diseases, collectively termed the α-synucleinopathies, which includes Parkinson's disease. progression these diseases is, in part, mediated by extracellular oligomers that may exert effects through mechanisms, including prion-like transfer, direct cytotoxicity, and pro-inflammatory actions. In this study, we show two abundant chaperones, clusterin α2-macroglobulin, directly bind to exposed hydrophobic regions on surface...
TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids Aβ inducing an innate immune response. Missense mutations (e.g., R47H) of increase risk Alzheimer's disease (AD). The soluble ectodomain wild-type (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that oligomers bind cellular TREM2, shedding sTREM2 domain. Wild-type bound (measured by single-molecule imaging, dot blots, Bio-Layer...
Protein aggregation likely plays a key role in the initiation and spreading of Alzheimer's disease pathology through brain. Soluble aggregates amyloid beta are believed to play this process. However, present humans still poorly characterized due lack suitable methods required for characterizing low concentration heterogeneous present. We have used variety biophysical characterize human brains at Braak stage III. find soluble beta-containing all regions brain up 200 nm length, capable causing...
Studies on diffusion dynamics of single molecules (SMs) have been useful in revealing inhomogeneity polymer thin films near and above the glass-transition temperature (T(g)). However, despite several applications where exposure to solvent (or vapor) is common, effect absorbed local morphology rigidity matrices yet be explored detail. High-T(g) hydrophilic polymers such as poly(vinylpyrrolidone) (PVP) are used pharmaceutical coatings for drug release aqueous medium, they readily absorb...
The aberrant misfolding and subsequent conversion of monomeric protein into amyloid aggregates characterises many neurodegenerative disorders, including Parkinson's Alzheimer's diseases. These are highly heterogeneous in structure, generally low abundance typically smaller than the diffraction limit light (≈250 nm). To overcome challenges these characteristics pose to study endogenous formed cells, we have developed a method characterise them at nanometre scale without need for conjugated...
We combine the techniques of infrared multiphoton dissociation (IRMPD) with state selective ion imaging to probe roaming dynamics in unimolecular nitromethane and methyl nitrite. Recent theoretical calculations suggest a "roaming-mediated isomerization" pathway nitrite prior decomposition. State-resolved NO product coupled was carried out examine this decomposition near threshold. The IRMPD images for from are consistent earlier studies that first suggested importance an isomerization...
Abstract The high light‐output efficiencies of In x Ga 1‐ N quantum‐well (QW)‐based light‐emitting diodes (LEDs) even in presence a large number nonradiative recombination centers (such as dislocations) has been explained by localization carriers radiative potential traps, the origins which still remain unclear. To provide insights on highly efficient spectrally resolved photoluminescence (PL) microscopy performed green‐light‐emitting 0.22 0.78 QW LEDs, selectively generating alloy layers....
The nature of the polarization-field in disorder induced nanoscale potential fluctuations (radiative traps) within (In,Ga)N based quantum-well (QW) heterostructures remains ambiguous. Spectrally resolved photoluminescence microscopy has been utilized to probe local polarization field by monitoring extent quantum-confined Stark effect (QCSE) radiative trap centers spontaneously formed an QW light emitting diode. Interestingly, two distinct categories domains, which arise from indium...
Abstract Small aggregates of misfolded proteins play a key role in neurodegenerative disorders. Such species have proved difficult to study due the lack suitable methods capable resolving these heterogeneous aggregates, which are smaller than optical diffraction limit. We demonstrate here an all‐optical fluorescence microscopy method characterise structure individual protein based on anisotropy dyes such as thioflavin‐T, and show that this technology is studying oligomers human biofluids...
Small oligomers of the protein α-synuclein (αS) are highly cytotoxic species associated with Parkinson's disease (PD). In addition, αS can form co-aggregates its mutational variants and other proteins such as amyloid-β (Aβ) tau, which implicated in Alzheimer's disease. The processes self-oligomerization co-oligomerization are, however, challenging to study quantitatively. Here, we have utilized single-molecule techniques measure equilibrium populations formed vitro by mixtures wild-type...
The intrinsic spectral line widths of defect-related transitions in quantum-confined semiconductor nanocrystals are often difficult to estimate using ensemble measurements because the extent inhomogeneous broadening due particle size distributions is not known precisely. To address this problem, we performed spectrally resolved photoluminescence (PL) microscopy individual ZnO NC by directly populating defects states low-energy laser excitation. temporal evolution PL intensities shows...
Determining the structure-function relationships of protein aggregates is a fundamental challenge in biology. These aggregates, whether formed vitro, within cells, or living organisms, present significant heterogeneity their molecular features such as size, structure, and composition, making it difficult to determine how structure influences functions. Interpreting these translate into functional roles crucial for understanding cellular homeostasis pathogenesis various debilitating diseases...