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Professor Tuomas Knowles

University Position
Professor

Interests

We work on the physico-chemical properties and behaviour of biological molecules and soft materials. The research in the group is highly interdisciplinary. Members of the group have a wide range of backgrounds. We used methods from biochemistry, chemistry, chemical engineering and physics, and work in close collaboration with other groups in Cambridge and overseas. We apply new physical methods to understand the misfolding and aggregation of proteins molecules into amyloid fibrils of the type encountered in neurodegenerative disorders. The techniques used in our laboratory include biosensors, optical lithography, microfluidic devices and scanning probe microscopy and spectroscopy. We also have an interest in applying theoretical concepts from statistical mechanics and chemical kinetics to protein systems.

Key Publications

Structure-specific amyloid precipitation in biofluids.

DOI: http://doi.org/10.1038/s41557-022-00976-3
Journal: Nat Chem
E-pub date: 1 Sep 2022
Authors: M Rodrigues, P Bhattacharjee, A Brinkmalm, DT Do, CM Pearson, S De, A Ponjavic, JA Varela, K Kulenkampff, I Baudrexel, D Emin, FS Ruggeri, JE Lee, AR Carr, TPJ Knowles, H Zetterberg, TN Snaddon, S Gandhi, SF Lee, D Klenerman

The Pathological G51D Mutation in Alpha-Synuclein Oligomers Confers Distinct Structural Attributes and Cellular Toxicity.

DOI: http://doi.org/10.3390/molecules27041293
Journal: Molecules
E-pub date: 15 Feb 2022
Authors: CK Xu, M Castellana-Cruz, SW Chen, Z Du, G Meisl, A Levin, B Mannini, LS Itzhaki, TPJ Knowles, CM Dobson, N Cremades, JR Kumita

Phase Separation of FUS is Modulated by Methylation State of Cation-π Interactions and Interaction with TNPO1

DOI: http://doi.org/10.1016/j.cell.2018.03.056
Journal: Cell
E-pub date: 19 Apr 2018
Authors: PH St George-Hyslop, S Qamar, G Wang, SJ Randle, FS Ruggeri, J Varela, CF Kaminski, GS Kaminski, M Vendruscolo, TPJ Knowles, D Klenerman, CE Holt, Q Lin, W meadows

Direct observation of the interconversion of normal and toxic forms of α-synuclein.

DOI: http://doi.org/10.1016/j.cell.2012.03.037
Journal: Cell
E-pub date: 25 May 2012
Authors: N Cremades, SIA Cohen, E Deas, AY Abramov, AY Chen, A Orte, M Sandal, RW Clarke, P Dunne, FA Aprile, CW Bertoncini, NW Wood, TPJ Knowles, CM Dobson, D Klenerman

Publications

Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

DOI: http://doi.org/10.1038/s41467-022-33252-6
Journal: Nature Communications
E-pub date: 20 Sep 2022
Authors: D Emin, YP Zhang, E Lobanova, A Miller, X Li, Z Xia, H Dakin, DI Sideris, JYL Lam, RT Ranasinghe, A Kouli, Y Zhao, S De, TPJ Knowles, M Vendruscolo, FS Ruggeri, FI Aigbirhio, CH Williams-Gray, D Klenerman

Rate‐limiting processes of tau aggregate accumulation in Alzheimer’s disease

DOI: http://doi.org/10.1002/alz.051680
Journal: Alzheimer's & Dementia
E-pub date: 1 Dec 2021
Authors: G Meisl, Y Zuo, K Allinson, T Rittman, SL DeVos, JS Sanchez, CK Xu, KE Duff, KA Johnson, JB Rowe, BT Hyman, T Knowles, D Klenerman

In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease.

DOI: http://doi.org/10.1126/sciadv.abh1448
Journal: Sci Adv
E-pub date: 29 Oct 2021
Authors: G Meisl, E Hidari, K Allinson, T Rittman, SL DeVos, JS Sanchez, CK Xu, KE Duff, KA Johnson, JB Rowe, BT Hyman, TPJ Knowles, D Klenerman

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers.

DOI: http://doi.org/10.3389/fnins.2021.680026
Journal: Front Neurosci
E-pub date: 1 Aug 2021
Authors: R Limbocker, R Staats, S Chia, FS Ruggeri, B Mannini, CK Xu, M Perni, R Cascella, A Bigi, LR Sasser, NR Block, AK Wright, RP Kreiser, ET Custy, G Meisl, S Errico, J Habchi, P Flagmeier, T Kartanas, JE Hollows, LT Nguyen, K LeForte, D Barbut, JR Kumita, C Cecchi, M Zasloff, TPJ Knowles, CM Dobson, F Chiti, M Vendruscolo

A dopamine metabolite stabilizes neurotoxic amyloid-β oligomers.

DOI: http://doi.org/10.1038/s42003-020-01490-3
Journal: Commun Biol
E-pub date: 4 Jan 2021
Authors: R Cataldi, S Chia, K Pisani, FS Ruggeri, CK Xu, T Šneideris, M Perni, S Sarwat, P Joshi, JR Kumita, S Linse, J Habchi, TPJ Knowles, B Mannini, CM Dobson, M Vendruscolo

Rapid Structural, Kinetic, and Immunochemical Analysis of Alpha-Synuclein Oligomers in Solution.

DOI: http://doi.org/10.1021/acs.nanolett.0c03260
Journal: Nano Lett
E-pub date: 11 Nov 2020
Authors: WE Arter, CK Xu, M Castellana-Cruz, TW Herling, G Krainer, KL Saar, JR Kumita, CM Dobson, TPJ Knowles

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism.

DOI: http://doi.org/10.1038/s42003-020-01140-8
Journal: Commun Biol
E-pub date: 13 Aug 2020
Authors: R Limbocker, B Mannini, FS Ruggeri, R Cascella, CK Xu, M Perni, S Chia, SW Chen, J Habchi, A Bigi, RP Kreiser, AK Wright, JA Albright, T Kartanas, JR Kumita, N Cremades, M Zasloff, C Cecchi, TPJ Knowles, F Chiti, M Vendruscolo, CM Dobson

The Influence of Pathogenic Mutations in α-Synuclein on Biophysical and Structural Characteristics of Amyloid Fibrils.

DOI: http://doi.org/10.1021/acsnano.9b09676
Journal: ACS Nano
E-pub date: 26 May 2020
Authors: FS Ruggeri, P Flagmeier, JR Kumita, G Meisl, DY Chirgadze, MN Bongiovanni, TPJ Knowles, CM Dobson

Fabrication and Characterization of Reconstituted Silk Microgels for the Storage and Release of Small Molecules.

DOI: http://doi.org/10.1002/marc.201800898
Journal: Macromol Rapid Commun
E-pub date: 1 Apr 2019
Authors: X Liu, Z Toprakcioglu, AJ Dear, A Levin, FS Ruggeri, CG Taylor, M Hu, JR Kumita, M Andreasen, CM Dobson, U Shimanovich, TPJ Knowles

Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

DOI: http://doi.org/10.1038/s41467-018-07699-5
Journal: Nat Commun
E-pub date: 15 Jan 2019
Authors: R Limbocker, S Chia, FS Ruggeri, M Perni, R Cascella, GT Heller, G Meisl, B Mannini, J Habchi, TCT Michaels, PK Challa, M Ahn, ST Casford, N Fernando, CK Xu, ND Kloss, SIA Cohen, JR Kumita, C Cecchi, M Zasloff, S Linse, TPJ Knowles, F Chiti, M Vendruscolo, CM Dobson

Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine.

DOI: http://doi.org/10.1021/acschembio.8b00466
Journal: ACS Chem Biol
E-pub date: 17 Aug 2018
Authors: M Perni, P Flagmeier, R Limbocker, R Cascella, FA Aprile, C Galvagnion, GT Heller, G Meisl, SW Chen, JR Kumita, PK Challa, JB Kirkegaard, SIA Cohen, B Mannini, D Barbut, EAA Nollen, C Cecchi, N Cremades, TPJ Knowles, F Chiti, M Zasloff, M Vendruscolo, CM Dobson

Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes.

DOI: http://doi.org/10.1038/s41557-018-0031-x
Journal: Nat Chem
E-pub date: 1 Jun 2018
Authors: J Habchi, S Chia, C Galvagnion, TCT Michaels, MMJ Bellaiche, FS Ruggeri, M Sanguanini, I Idini, JR Kumita, E Sparr, S Linse, CM Dobson, TPJ Knowles, M Vendruscolo

Inhibition of α-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α-Synuclein Species.

DOI: http://doi.org/10.1021/acs.biochem.6b01178
Journal: Biochemistry
E-pub date: 7 Mar 2017
Authors: FA Aprile, P Arosio, G Fusco, SW Chen, JR Kumita, A Dhulesia, P Tortora, TPJ Knowles, M Vendruscolo, CM Dobson, N Cremades

Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease.

DOI: http://doi.org/10.1073/pnas.1615613114
Journal: Proc Natl Acad Sci U S A
E-pub date: 10 Jan 2017
Authors: J Habchi, S Chia, R Limbocker, B Mannini, M Ahn, M Perni, O Hansson, P Arosio, JR Kumita, PK Challa, SIA Cohen, S Linse, CM Dobson, TPJ Knowles, M Vendruscolo

Population of nonnative states of lysozyme variants drives amyloid fibril formation.

DOI: http://doi.org/10.1021/ja109620d
Journal: J Am Chem Soc
E-pub date: 25 May 2011
Authors: AK Buell, A Dhulesia, MF Mossuto, N Cremades, JR Kumita, M Dumoulin, ME Welland, TPJ Knowles, X Salvatella, CM Dobson

Methods and models in neurodegenerative and systemic protein aggregation diseases.

DOI: http://doi.org/10.2741/3626
Journal: Front Biosci (Landmark Ed)
E-pub date: 1 Jan 2010
Authors: A-C Brorsson, JR Kumita, I MacLeod, B Bolognesi, E Speretta, LM Luheshi, TPJ Knowles, CM Dobson, DC Crowther