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Centre for Misfolding Diseases

Director of Research

  • The late Professor Sir Christopher Dobson died on 8th September 2019. Chris was not only a world-class researcher whose work helped to advance the global understanding of conditions such as Alzheimer’s and Parkinson’s diseases, but also a kind and compassionate man who encouraged many aspiring scientists and built a wide network of collaborators in this research field. (You can see his obituary on our website here.) Although he has died, the research described below continues within the Centre for Misfolding Diseases, part of the Chemistry of Health building – a state-of-the-art facility for the study of neurodegenerative diseases that he was instrumental in creating.

Our research interests are primarily focused on the investigation of the structures and properties of biological molecules, especially proteins, and their relationship to biological evolution and disease. We have particular interest in the fundamental science underlying disorders such as Alzheimer's and Parkinson's disease. In addition, however, we have recently become involved in the novel utilisation of biological molecules in materials science and nanotechnology.

The methods we use are largely experimental, but do include theoretical and computational approaches. Much of the work is highly interdisciplinary, and people joining the group come from a wide variety of scientific backgrounds ranging from experimental biochemistry to theoretical physics. The research group is based in the Chemistry Department in a newly constructed laboratory located in the Unilever Building. The range of experimental techniques used by the group is very large, including NMR, EM, AFM and X-ray diffraction, as well as a variety of methods based on optical spectroscopy, including fluorescence and circular dichroism. Many, but not all, members of the group also use the techniques of protein chemistry and molecular biology.

The group has close links with scientists in other laboratories in Cambridge, including the Clinical School, the Genetics Department and the Nanoscience Centre and, indeed, some members of the group have been largely based in these departments. New members of the group usually develop a project by discussion with me, along with other members of the research team. Group members are often involved in joint projects with other laboratories and may spend periods of time working with our collaborators in other parts of the world.

More information: Chris Dobson full CV (Microsoft Word)(PDF);Chris Dobson Publications list(Microsoft Word)(PDF).

The following articles provide a general appreciation of our current areas of research:

Reviews

F. Chiti and C.M. Dobson, "Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade" Annu Rev Biochem, 86, 27-68 (2017).

N. Cremades, S.W. Chen and C.M. Dobson, "Structural characteristics of α-synuclein oligomers" Int Rev Cell Mol Biol, 329, 79-143 (2017).

T.P.J. Knowles, M. Vendruscolo and C.M. Dobson, "The physical basis of protein misfolding disorders" Physics Today, 68, 36-41 (2015).

T.P.J. Knowles, M. Vendruscolo and C.M. Dobson. “The Amyloid State and its Association with Protein Misfolding Diseases”, Nature Rev Mol Cell Biol, 15, 384-396 (2014).  

E.P. O’Brien, P. Ciryam, M. Vendruscolo and C.M. Dobson, “Understanding the influence of codon translation rates on cotranslational protein folding” Acc Chem Res, 47, 1536-44 (2014).

S.I. Cohen, M. Vendruscolo, C.M. Dobson and T.P. Knowles, "From macroscopic measurements to microscopic mechanisms of protein aggregation" J Mol Biol, 41, 160-171 (2012).

L.D. Cabrita, C.M. Dobson, and J. Christodoulou, "Protein folding on the ribosome" Curr Opin Struct Biol,  20, 33-45 (2010).

F. Chiti and C.M. Dobson, Amyloid Formation by Globular Proteins under Native Conditions, Nature Chem Biol, 5, 15-22 (2009)

L.M. Luheshi, D.C. Crowther and C.M. Dobson, Protein Misfolding and Disease: From the Test Tube to the Organism, Curr Opin Chem Biol, 12, 25-31 (2008)

M. Vendruscolo and C.M. Dobson, Dynamic Visions of Enzymatic Reactions, Science, 313, 1586- 1587 (2006)

F. Chiti and C.M. Dobson, Protein Misfolding, Functional Amyloid and Human Disease, Annu Rev Biochem, 75, 333-366 (2006)

C.M. Dobson, Chemical Space and Biology, Nature, 432, 824-882 (2004)

C.M. Dobson, Protein Folding and Misfolding, Nature, 426, 884-890 (2003)

C.M. Dobson, Protein Misfolding, Evolution and Disease, Trends Biochem Sci, 24, 329-332 (1999)

C.M. Dobson, A. Sali and M. Karplus, Protein Folding: A Perspective from Theory and Experiment, Angew Chem Int Ed Eng, 37, 868-893 (1998)

Selected Publications

G. Fusco, S.W. Chen, P.T.F. Williamson, R. Cascella, M. Perni, J.A. Jarvis, C. Cecchi, M. Vendruscolo, F. Chiti, N. Cremades, L. Ying, C.M. Dobson and A. De Simone, "Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers" Science, 358, 1440-1443 (2017).

R. Kundra, P. Ciryam, R.I. Morimoto, C.M. Dobson CM and Vendruscolo M, "Protein homeostasis of a metastable subproteome associated with Alzheimer's disease" Proc Natl Acad Sci USA, 114, E5703-E5711 (2017).

J. Habchi, P. Arosio, M. Perni, A.R. Costa, M. Yagi-Utsumi, P. Joshi, S. Chia, S.I. Cohen, M.B. Müller, S. Linse, E.A. Nollen, C.M. Dobson, T.P.J. Knowles and M. Vendruscolo, "An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease" Sci Adv, 2, e1501244 (2016).

L.D. Cabrita, A.M. Cassaignau, H.M. Launay, C.A. Waudby, T. Wlodarski, C. Camilloni, M.E. Karyadi, A.L. Robertson, X. Wang, A.S. Wentink, L.S. Goodsell, C.A. Woolhead, M. Vendruscolo, C.M. Dobson and J. Christodoulou, "A structural ensemble of a ribosome-nascent chain complex during cotranslational protein folding" Nat Struct Mol Biol, 23, 278-85 (2016).

S.I. Cohen, P. Arosio, J. Presto, F.R. Kurudenkandy, H. Biverstål, L. Dolfe, C. Dunning, X. Yang, B. Frohm, M. Vendruscolo, J. Johansson, C.M. Dobson, A. Fisahn, T.P.J. Knowles and S. Linse, "A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers" Nat Struct Mol Biol, 22, 207-213 (2015).

C. Galvagnion, A.K. Buell, G. Meisl,T.C. Michales, M. Vendruscolo, T.P.J. Knowles and C.M. Dobson, "Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation" Nat Chem Biol, 11, 229-234 (2015).

A.W. Fitzpatrick, G.T. Debelouchina, M.J. Bayro, D.K. Clare, M.A. Caparoni, V.S. Bajaj, C.P. Jaroniec, L. Wang, V. Ladizhansky, S.A. Muller, C.E. MacPhee, C.A. Waudby, H. Mott, A. de Simone, T.P.J. Knowles, H.R. Saibil, M. Vendruscolo, E. Orlova, R.G.Griffin and C.M. Dobson, “Atomic-resolution Structure of a Cross-b  Amyloid Fibril”, Proc Natl Acad Sci USA, 110, 5468-5473 (2013).

S.I. Cohen, S. Linse, L.M. Luheshi, E. Hellstrand, D.A. White, L. Rajah, D.E. Otzen, M. Vendruscolo, C.M. Dobson and T.P. Knowles, "Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism", Proc Natl Acad Sci USA 110, 9758-9763 (2013).

N. Cremades, S.I. Cohen, E. Deas, A.Y. Abramov, A.Y. Chen, A. Orte, M. Sandal, R.W. Clarke, P. Dunne, F.A. Aprile, C.W. Bertoncini, N.W. Wood, T.P. Knowles, C.M. Dobson and D. Klenerman. "Direct Observation of the Interconversion of Normal and Toxic Forms of α- Synuclein", Cell 149, 1048-1059 (2012).

A. De Simone, A. Dhulesia, G. Soldi, M. Vendruscolo, S.T. Hsu, F. Chiti, and C.M. Dobson, "Experimental Free Energy Surfaces Reveal the Mechanisms of Maintenance of Protein Solubility", Proc Natl Acad Sci USA 108, 21057-21062 (2011).

T.P.J. Knowles, C.A. Waudby, G.L. Devlin, S.A. Cohen, A. Aguzzi, M. Vendruscolo, E.M. Terentjev, M.E. Welland and C.M. Dobson, An Analytical Solution to the Kinetics of Breakable Filament Assembly, Science 326, 1533-1537 (2009)

S.T. Hsu, L.D. Cabrita, P. Fucini, J. Christodoulou and C.M. Dobson, Probing Side-chain Dynamics of a Ribosome-bound Nascent Chain using Methyl NMR Spectroscopy, J. Am. Chem. Soc., 131 (24), 8366-8367, (2009)

T.P. Knowles, A.W. Fitzpatrick, S. Meehan, H.R. Mott, M. Vendruscolo, C.M. Dobson and M.E. Welland, Role of Intermolecular Forces in Defining Material Properties of Protein Nanofibrils, Science 318, 1900-1903 (2007)

L.M. Luheshi, G.G. Tartaglia, A.C. Brorsson, A.P. Pawar, I.E. Watson, F. Chiti, M. Vendruscolo, D.A. Lomas, C.M. Dobson and D.C. Crowther, Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid Beta Pathogenicity, PloS Biol. 5(11):e290 (2007)

K. Lindorff-Larsen, R.B. Best, M.A. De Pristo, C.M. Dobson and M. Vendruscolo, Simultaneous Determination of Protein Structure and Dynamics, Nature 433, 129-133 (2005)

D.M. Korzhnev, X. Salvatella, M. Vendruscolo, A.A. Di Nardo, A.R. Davison, C.M. Dobson and L.E. Kay, Low Populated Folding Intermediates of the Fyn SH3 Domain Characterized by Relaxation Dispersion NMR, Nature 430, 586-590 (2004)

M. Dumoulin, A.M. Last, A. Desmyter, K. Decanniere, D. Canet, A. Spencer, D.B. Archer, S. Muyldermans, L. Wyns, A. Matagne, C. Redfield, C.V. Robinson and C.M. Dobson, A Camelid Antibody Fragment Inhibits Amyloid Fibril Formation by Human Lysozyme, Nature 424, 783-788 (2003)

F. Chiti, M. Stefani, N. Taddei, G. Ramponi and C.M. Dobson, Rationalisation of Mutational Effects on Protein Aggregation Rates, Nature 424, 805-808 (2003)

M. Fändrich, M.A. Fletcher and C.M. Dobson, Amyloid Fibrils from Muscle Myoglobin, Nature 410, 165-166 (2001)

M. Vendruscolo, E. Paci, C.M. Dobson and M. Karplus, Three Key Residues Form a Critical Contact Network in a Transition State for Protein Folding, Nature 409, 641-646 (2001)

Publications

The Amyloid Phenomenon and Its Significance in Biology and Medicine
CM Dobson, TPJ Knowles, M Vendruscolo
– Cold Spring Harb Perspect Biol
(2020)
12,
a033878
Trodusquemine enhances Aβ
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
– Nature communications
(2019)
10,
225
Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification.
PR Lindstedt, FA Aprile, MJ Matos, M Perni, JB Bertoldo, B Bernardim, Q Peter, G Jiménez-Osés, TPJ Knowles, CM Dobson, F Corzana, M Vendruscolo, GJL Bernardes
– ACS central science
(2019)
5,
1417
An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
ED Agerschou, P Flagmeier, T Saridaki, C Galvagnion, D Komnig, L Heid, V Prasad, H Shaykhalishahi, D Willbold, CM Dobson, A Voigt, B Falkenburger, W Hoyer, AK Buell
– eLife
(2019)
8,
e46112
Differential interactome and innate immune response activation of two structurally distinct misfolded protein oligomers.
B Mannini, G Vecchi, A Labrador-Garrido, B Fabre, G Fani, JM Franco, K Lilley, D Pozo, M Vendruscolo, F Chiti, CM Dobson, C Roodveldt
– ACS Chem Neurosci
(2019)
10,
3464
Nature and Regulation of Protein Folding on the Ribosome.
CA Waudby, CM Dobson, J Christodoulou
– Trends in biochemical sciences
(2019)
44,
914
The Toxicity of Misfolded Protein Oligomers Is Independent of Their Secondary Structure.
M Vivoli Vega, R Cascella, SW Chen, G Fusco, A De Simone, CM Dobson, C Cecchi, F Chiti
– ACS Chem Biol
(2019)
14,
1593
Fast Fluorescence Lifetime Imaging Reveals the Aggregation Processes of α-Synuclein and Polyglutamine in Aging Caenorhabditis elegans.
RF Laine, T Sinnige, KY Ma, AJ Haack, C Poudel, P Gaida, N Curry, M Perni, EAA Nollen, CM Dobson, M Vendruscolo, GS Kaminski Schierle, CF Kaminski
– ACS Chem Biol
(2019)
14,
1628
Expression of the amyloid-β peptide in a single pair of C. elegans sensory neurons modulates the associated behavioural response.
T Sinnige, P Ciryam, S Casford, CM Dobson, M de Bono, M Vendruscolo
– PLoS One
(2019)
14,
e0217746
Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice
JM Froula, M Castellana-Cruz, NM Anabtawi, JD Camino, SW Chen, DR Thrasher, J Freire, AA Yazdi, S Fleming, CM Dobson, JR Kumita, N Cremades, LA Volpicelli-Daley
– The Journal of biological chemistry
(2019)
294,
jbc.RA119.007743
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Former Director

Telephone number

01223 763070 (shared)