Sheffield Institute for
Translational Neuroscience

Dr Suman De

Research Fellow

UKRI Future Leaders Fellow


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.

Current Projects

  1. Interaction of Amyloid-β and Apolipoprotein in Alzhimer’s disease
  2. Protein-aggregate membrane interaction in health and disease
  3. Misfolded and aggregated conformational strains in Neurodegenerative Diseases
  4. Identificaton and charecterisation of protein aggregates in human biofluids and post-mortem tissue

Publications

Detail publication list : Google Scholar

Selected Publications

  1. Flagmeier P*, De S*, Michaels TCT*, Emanuelsson C, Vendruscolo M, Linse S, D. Klenerman D, Knowles TPJ, Dobson CM; Direct measurements of lipid membrane disruption link Aβ42 amyloid formation and toxicity; Nature Structural and Molecular Biology 2020, 27, 886 (* Equal contribution) DOI: 10.1038/s41594-020-0471-z
  2. Whiten DR, Brownjohn PW, Moore S, De S, Strano A, Zuo Y, Haneklaus M, Klenerman D, Livesey FJ; TNF induces increased production of extracellular Aβ and α-synuclein-containing aggregates by human Alzheimer’s disease neurons; Brain Communication 2020, 2, fca146 DOI: 10.1093/braincomms/fcaa146
  3. Angelova P, Berezhnov A, Horrocks M, Hughes C, De S, Little K, Dolt K, Sylantiev S, Pavlov E, Klenerman D, Abramov A, Gandhi S; Alpha-synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation. Cell Death and Differentiation 2020, 27, 2781 – DOI: 10.1038/s41418-020-0542-z
  4. Sanderson JB, De S, Jiang H, Rover M, Jin M, Lagomarsino VN, Young-Pearse TL, Pochapsky T, Hyman B, Klenerman D, Selkoe DJ, Bartels T; Analysis of α-Synuclein Species Isolated from Lewy Body-positive Human Brain Cortex Brain Communication, 2020.2, fcaa010 DOI: 10.1093/braincomms/fcaa010
  5. De S*, Whiten DR*, Ruggeri FS*,  Hughes C, Rodrigues M, Sideris DI, Taylor DG, Aprile FA, Muyldermans S, Knowles TPJ, M. Vendruscolo M, Bryant CE, Blennow K, Skoog I,  Kern S, Zetterberg H, Klenerman D; Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression; Acta Neuropathologica Communication. 2019,7,120 (* Equal contribution) DOI: 10.1186/s40478-019-0777-4
  6. De S *, Wirthensohn DC *, Flagmeier P *, Hughes C *, Aprile FA, Ruggeri FS, Whiten DR, Emin D, Xia Z, Varela JA, Sormanni P, Kundel F, Knowles TPJ, Dobson CM, C. Bryant, M. Vendruscolo M, Klenerman D; Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms;  Nature Communication, 2019, 10, 1541 (* Equal contribution) DOI: 10.1038/s41467-019-09477-3
  7. De S and Klenerman D; Imaging individual protein aggregates to follow aggregation and determine the role of aggregates in neurodegenerative disease; Biochimica et Biophysica Acta Proteins and Proteomics 2019, 1867, 870 DOI: 10.1016/j.bbapap.2018.12.010
  8. Lee JE, Sang JC, Rodrigues M, Carr AR, Horrocks MH, De S, Bongiovanni MN, Flagmeier P, Dobson CM, Wales DJ, Lee SF, Klenerman D; Mapping Surface Hydrophobicity of α-Synuclein Oligomers at the Nanoscale; Nano Letters., 2018, 18,7494 DOI: 10.1021/acs.nanolett.8b02916
  9. Iljina M, Dear AJ, Garcia AG, De S, Tosatto L, Flagmeier P, Whiten DR, Michaels TCT, Frenkel D, Dobson CM, Knowles TPJ, Klenerman D; Quantifying Co-Oligomer Formation by α-Synuclein; ACS NANO, 2018, 12,10855 DOI: /10.1021/acsnano.8b03575
  10. Whiten DR, Cox D, Horrocks MH, Taylor CG, De S, Flagmeier P, Tosatto L, Kumita JR, Ecroyd H, Dobson CM, Klenerman D, Wilson MR; Single-Molecule Characterisation of the Interactions between Extracellular Chaperones and Toxic α-Synuclein Oligomers; Cell Reports 2018, 23, 3492 DOI: 10.1016/j.celrep.2018.05.074
  11. Varela JA, Rodrigues M, De S, Flagmeier P, Gandhi S, Dobson CM, Klenerman D, Lee SF; Optical structural analysis of individual α-synuclein oligomers; Angewandte Chemie - Int. Ed. 2018, 57, 4886 DOI: 10.1002/anie.201710779
  12. F. Kundel F, De S, Flagmeier P, Horrocks MH, Kjaergaard M, Shammas S, Jackson SE, Dobson CM, D. Klenerman D; Hsp70 inhibits the nucleation and elongation of tau and sequesters tau aggregates with high affinity; ACS Chemical Biology 2018, 13, 636. DOI: 10.1021/acschembio.7b01039
  13. Drews A *, De S *, FlagmeierP *, Wirthensohn DC, Chen WH, Whiten DR, Rodrigues M, Vincke C, Muyldermans S, Paterson RW, Slattery CF, Fox NC, Schott JM, Zetterberg H, Dobson CM, Klenerman D; Inhibiting the Ca2+ influx induced by human CSF; Cell Reports. 2017, 21, 3310. DOI: 10.1016/j.celrep.2017.11.057 (* Equal contribution)
  14. Ultrasensitive measurement of Ca2+ influx into lipid vesicles induced by protein aggregates; Flagmeier F *, De S *, Wirthensohn DC, Lee SF, Vincke C, Muyldermans S, Knowles TPJ, Gandhi S, Dobson CM, Klenerman D Angewandte Chemie - Int. Ed, 2017, 26, 7750 (* Equal contribution) DOI: 10.1002/anie.201700966

Awards

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

Contact Details

Department of Neuroscience
SITraN, Room B28
University of Sheffield
385a Glossop Road
Sheffield
S10 2HQ

E: s.de@sheffield.ac.uk
T: +44 (0)114 21 59107