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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

Probing the Origin of the Toxicity of Oligomeric Aggregates of α‑Synuclein with Antibodies
R Cascella, M Perni, SW Chen, G Fusco, C Cecchi, M Vendruscolo, F Chiti, CM Dobson, A De Simone
– ACS Chemical Biology
(2019)
14,
1352
Determination of the structural ensemble of the molten globule state of a protein by computer simulations
M Shimizu, Y Kajikawa, K Kuwajima, CM Dobson, Y Okamoto
– Proteins Structure Function and Bioinformatics
(2019)
87,
635
Identifying A- and P-site locations on ribosome-protected mRNA fragments using Integer Programming
N Ahmed, P Sormanni, P Ciryam, M Vendruscolo, CM Dobson, EP O'Brien
– Sci Rep
(2019)
9,
6256
Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates
T Scheidt, U Łapińska, JR Kumita, DR Whiten, D Klenerman, MR Wilson, SIA Cohen, S Linse, M Vendruscolo, CM Dobson, TPJ Knowles, P Arosio
– Science Advances
(2019)
5,
eaau3112
Biophysical Techniques in Structural Biology
CM Dobson
– ANNUAL REVIEW OF BIOCHEMISTRY, VOL 88
(2019)
88,
25
Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
S De, DC Wirthensohn, P Flagmeier, C Hughes, FA Aprile, FS Ruggeri, DR Whiten, D Emin, Z Xia, JA Varela, P Sormanni, F Kundel, TPJ Knowles, CM Dobson, C Bryant, M Vendruscolo, D Klenerman
– Nature communications
(2019)
10,
1541
The metastability of the proteome of spinal motor neurons underlies their selective vulnerability in ALS
JJ Yerbury, L Ooi, IP Blair, P Ciryam, CM Dobson, M Vendruscolo
– Neuroscience letters
(2019)
704,
89
Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer'sassociated amyloid beta peptide
JH Cater, JR Kumita, R Zeineddine Abdallah, G Zhao, A Bernardo-Gancedo, A Henry, W Winata, M Chi, BSF Grenyer, ML Townsend, M Ranson, CS Buhimschi, DS Charnock-Jones, CM Dobson, MR Wilson, IA Buhimschi, AR Wyatt
– Proceedings of the National Academy of Sciences of the United States of America
(2019)
116,
6101
Increased Secondary Nucleation Underlies Accelerated Aggregation of the Four-Residue N-Terminally Truncated Aβ42 Species Aβ5-42.
T Weiffert, G Meisl, P Flagmeier, S De, CJR Dunning, B Frohm, H Zetterberg, K Blennow, E Portelius, D Klenerman, CM Dobson, TPJ Knowles, S Linse
– ACS Chemical Neuroscience
(2019)
10,
2374
Fabrication and Characterization of Reconstituted Silk Microgels for the Storage and Release of Small Molecules
X Liu, Z Toprakcioglu, AJ Dear, A Levin, FS Ruggeri, CG Taylor, M Hu, JR Kumita, M Andreasen, CM Dobson, U Shimanovich, TPJ Knowles
– Macromolecular rapid communications
(2019)
40,
e1800898
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Former Director

Telephone number

01223 763070 (shared)