Neuroscience, School of Medicine and Population Health
UKRI Future Leaders Fellow
+44 114 21 59107
Full contact details
Neuroscience, School of Medicine and Population Health
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
- Research interests
Identification and characterisation of protein complexes, aggregates and post-translational modifications in human is essential for understanding the underlying mechanism of a range of neurodegenerative disease including Alzheimer’s disease, Parkinson disease and Amyotrophic Lateral Sclerosis. In all these diseases, physiological form of proteins such as amyloid-β, α-synuclein, Tar DNA binding protein-43, under specific conditions, aggregate into a range of soluble complexes, and ultimately polymerising into insoluble fibrils to deposit in the specific parts of the central nervous system. These diseases associated proteins can potentially aggregate into many different forms, consisting of different numbers of peptides, with multiple possible post-translational modifications and co-aggregating species. Since the structural and compositional heterogeneities of these protein aggregate correlate with the disease type and severity, determination of specific molecular details of individual pathogenic aggregates is of vital importance.
In our group, we develop and apply novel imaging-based biophysical methodologies to identify and characterise these disease-associated protein aggregates at the single-molecule level with the goal of identifying the structural determinants of their pathogenicity, determining the primary molecular events that trigger their formation and finally, finding the right molecular approach to prevent their formation, block their neurotoxic effects or enhance their clearance. Single-molecule characterisation of these individual aggregates is crucial, especially in a scenario where toxicity may arise from a specific type of species, conformation, or pathways. By studying aggregation and propagation of disease-relevant proteins at the highest level of sensitivity, we aim to understand molecular mechanism underpinning various neurological disorders such as Alzheimer’s disease, Parkinson disease and Amyotrophic Lateral Sclerosis.
- Interaction of Amyloid-β and Apolipoprotein in Alzhimer’s disease
- Protein-aggregate membrane interaction in health and disease
- Misfolded and aggregated conformational strains in Neurodegenerative Diseases
- Identificaton and charecterisation of protein aggregates in human biofluids and post-mortem tissue
This person does not have any publications available.
- Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease. Nature Communications, 13(1).
- Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. Nature Neuroscience, 25(9), 1134-1148.
- Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses.. Nature Communications, 13.
- Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer’s disease. Brain Communications, 3(3).
- Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation. Journal of Biological Chemistry, 296, 100631-100631.
- Direct measurement of lipid membrane disruption connects kinetics and toxicity of Aβ42 aggregation. Nature Structural & Molecular Biology, 27(-), 886-891. View this article in WRRO
- TNF induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer’s disease neurons. Brain Communications. View this article in WRRO
- Correction: Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation. Cell Death & Differentiation, 27(9), 2747-2747.
- Alpha synuclein aggregation drives ferroptosis : an interplay of iron, calcium and lipid peroxidation. Cell Death & Differentiation. View this article in WRRO
- Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies. Brain Communications, 2(1). View this article in WRRO
- Tracking Oligomerization of Alpha-Synuclein Demonstrates Pivotal Role of Mitochondria in Seeding. Biophysical Journal, 118(3), 217a-217a.
- Imaging individual protein aggregates to follow aggregation and determine the role of aggregates in neurodegenerative disease. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1867(10), 870-878. View this article in WRRO
- Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer’s disease progression. Acta Neuropathologica Communications, 7(1). View this article in WRRO
- O3-01-03: MECHANISM OF TOXICITY INDUCED BY AMYLOID-BETA AGGREGATES CHANGES DURING THE PROGRESSION OF ALZHEIMER'S DISEASE. Alzheimer's & Dementia, 15, P875-P876.
- Increased Secondary Nucleation Underlies Accelerated Aggregation of the Four-Residue N-Terminally Truncated Aβ42 Species Aβ5–42. ACS Chemical Neuroscience, 10(5), 2374-2384.
- Direct observation of prion protein oligomer formation reveals an aggregation mechanism with multiple conformationally distinct species. Chemical Science, 10(17), 4588-4597. View this article in WRRO
- Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms. Nature Communications, 10(1), ---. View this article in WRRO
- Mapping surface hydrophobicity of α-synuclein oligomers at the nanoscale. Nano Letters, 18(12), 7494-7501. View this article in WRRO
- Quantifying co-oligomer formation by α-synuclein. ACS Nano, 12(11), 10855-10866. View this article in WRRO
- Nanoscopic characterisation of individual endogenous protein aggregates in human neuronal cells. ChemBioChem, 19(19), 2033-2038. View this article in WRRO
- Cover Feature: Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells (ChemBioChem 19/2018). ChemBioChem, 19(19), 2001-2001.
- Single-molecule characterization of the interactions between extracellular chaperones and toxic α-synuclein oligomers. Cell Reports, 23(12), 3492-3500. View this article in WRRO
- Optical structural analysis of individual α-synuclein oligomers. Angewandte Chemie International Edition, 57(18), 4886-4890. View this article in WRRO
- Optical Structural Analysis of Individual α-Synuclein Oligomers. Angewandte Chemie, 130(18), 4980-4984.
- Hsp70 inhibits the nucleation and elongation of tau and sequesters tau aggregates with high affinity. ACS Chemical Biology, 13(3), 636-646. View this article in WRRO
- O1‐01‐01: CHARACTERIZING PROTEIN AGGREGATES FROM THE HUMAN BRAIN. Alzheimer's & Dementia, 14(7S_Part_3).
- P2‐176: PROTEIN AGGREGATION AND NEUROINFLAMMATION ARE INTERRELATED IN ALZHEIMER'S DISEASE. Alzheimer's & Dementia, 14(7S_Part_13).
- Inhibiting the Ca 2+ influx induced by human CSF. Cell Reports, 21(11), 3310-3316. View this article in WRRO
- Developmentally regulated GTP binding protein 1 (DRG1) controls microtubule dynamics. Scientific Reports, 7(1). View this article in WRRO
- [P3-074]: AN ULTRA-SENSITIVE ASSAY TO MEASURE AGGREGATE INDUCED CA2+ INFLUX IN HUMAN CEREBROSPINAL FLUID. Alzheimer's & Dementia, 13(7S_Part_20), P960-P960.
- Ultrasensitive Measurement of Ca2+ Influx into Lipid Vesicles Induced by Protein Aggregates. Angewandte Chemie, 129(27), 7858-7862.
- Ultrasensitive measurement of Ca2+ influx into lipid vesicles induced by protein aggregates. Angewandte Chemie International Edition, 56(27), 7750-7754. View this article in WRRO
- Heterogeneity in optical properties of near white-light emissive europium complex species revealed by spectroscopy of single nanoaggregates. Chemical Physics Letters, 667, 247-253.
- Heterogeneity during Plasticization of Poly(vinylpyrrolidone): Insights from Reorientational Mobility of Single Fluorescent Probes. The Journal of Physical Chemistry B, 120(48), 12404-12415.
- Probing Differential Hydration of Poly(vinylpyrrolidone) Thin Films Using Tracer Mobility: An Insight from Fluorescence Correlation Spectroscopy. The Journal of Physical Chemistry B, 118(19), 5240-5249.
- Plasticization of Poly(vinylpyrrolidone) Thin Films under Ambient Humidity: Insight from Single-Molecule Tracer Diffusion Dynamics. The Journal of Physical Chemistry B, 117(25), 7771-7782.
- Quantum-confined stark effect in localized luminescent centers within InGaN/GaN quantum-well based light emitting diodes. Applied Physics Letters, 101(12), 121919-121919.
- Optoelectronic behaviors and carrier dynamics of individual localized luminescent centers in InGaN quantum-well light emitting diodes. Applied Physics Letters, 99(25), 251911-251911.
- Two Distinct Origins of Highly Localized Luminescent Centers within InGaN/GaN Quantum-Well Light-Emitting Diodes. Advanced Functional Materials, 21(20), 3828-3835.
- Light-Emitting Diodes: Two Distinct Origins of Highly Localized Luminescent Centers within InGaN/GaN Quantum-Well Light-Emitting Diodes (Adv. Funct. Mater. 20/2011). Advanced Functional Materials, 21(20), 3827-3827.
- Polarity selective etching: A self-assisted route for fabricating high density of c-axis oriented tapered GaN nanopillars. Journal of Applied Physics, 110(3), 033528-033528.
- Spectrally Resolved Photoluminescence Imaging of ZnO Nanocrystals at Single-Particle Levels. The Journal of Physical Chemistry Letters, 2(11), 1241-1247.
- Author Correction: Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. Nature Neuroscience.
- Structure-specific amyloid precipitation in biofluids. Nature Chemistry.
- Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite.
- Correction: Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation. Cell Death & Differentiation.
- An approach to estimate spatial distribution of analyte within cells using spectrally-resolved fluorescence microscopy. Methods and Applications in Fluorescence, 5(1), 014003-014003.
- Ultranarrow and Widely TunableMn2+-Induced Photoluminescence from Single Mn-Doped Nanocrystals of ZnS-CdS Alloys. Physical Review Letters, 110(26).
- Fast 3D imaging of giant unilamellar vesicles using re ected light-sheet microscopy with single molecule sensitivity. Journal of Microscopy.
- Custom-Made Microspheres for Optical Tweezers, Optical Tweezers (pp. 137-155). Springer New York
- Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1 expression, Cold Spring Harbor Laboratory.
- Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease, Research Square Platform LLC.
- Ultra-narrow and widely tunable Mn^(2+) Emission from Single Nanocrystals of ZnS-CdS alloy, arXiv.
- Structural conversion of α-synuclein at the mitochondria induces neuronal toxicity, Cold Spring Harbor Laboratory.
- Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease, Cold Spring Harbor Laboratory.
- Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent inflammatory responses, Research Square Platform LLC.
- Amyloid precipitation in biofluids using a structure-specific chemical antibody, Research Square Platform LLC.
- Fast 3D imaging of giant unilamellar vesicles using reflected light-sheet microscopy with single molecule sensitivity, Cold Spring Harbor Laboratory.
- ADSoluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer’s disease progression, Cold Spring Harbor Laboratory.
2022-2026: UKRI Future Leaders Fellowship
2021-2023: AMS Springboard Award
2019: Pilot Grant funded by Dementia Research Institute UK
2019: Pilot Grant funded Alzheimer’s Research UK
2016: Marie Curie Individual Fellowship funded by European Union