Professor of Biochemistry
4 South 1.46
Tel: +44 (0) 1225 383133
- Alzheimer's Research UK
- Dr. Jennifer McDowall
- Hazel Roberts
Prof David Brown
Our research focuses on proteins associated with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and the so called prion diseases. Prion diseases include the notorious Bovine Spongiform Encephalopathy and the human diseases vCJD, sporadic CJD and Fatal Familial Insomnia. However, despite the concern about these disease the prion protein is a harmless neuronal protein expressed in all vertebrates. Our group is concerned with the normal function of this protein. The prion protein is a copper binding protein which appears to be involved in cellular resistance to oxidative stress. Only when the protein is converted to an abnormal isoform is it capable of inducing neuronal death. Alpha-synuclein can also be converted to a toxic form by its interaction with copper. We are currently studying the mechanism of this process.
Research from our group has been instrumental in showing that the prion protein is a copper binding protein. Our current research includes new directions to study other metal binding proteins associated with neurodegenerative diseases. We have been studying the synuclein family of proteins and the copper and iron binding abilities. We are further investigating the metal binding of these proteins using exciting techniques such isothermal titration calorimetry, EPR and cyclic voltammetry. In particular, the redox chemistry of these proteins on binding metals is important to determine, as all three diseases are associated with oxidative damage to the brain.
We also use cell culture to investigate the function of proteins such as alpha-synuclein and APP. We have recently shown that alpha-synuclein is active in cells to reduce iron to Fe(II). We are investigating the further implications of this exciting breakthrough.
Professor Brown welcomes any enquires regarding Ph.D. opportunities. The group is also open to collaborations with other researchers or industrial partners.
McDowall, J. S. and Brown, D. R., 2016. Alpha-synuclein:relating metals to structure, function and inhibition. Metallomics, 8 (4), pp. 385-397.
Pass, R., Frudd, K., Barnett, J. P., Blindauer, C. A. and Brown, D. R., 2015. Prion infection in cells is abolished by a mutated manganese transporter but shows no relation to zinc. Molecular and Cellular Neuroscience, 68, pp. 186-193.
Goñi, F., Mathiason, C. K., Yim, L., Wong, K., Hayes-Klug, J., Nalls, A., Peyser, D., Estevez, V., Denkers, N., Xu, J., Osborn, D. A., Miller, K. V., Warren, R. J., Brown, D. R., Chabalgoity, J. A., Hoover, E. A. and Wisniewski, T., 2015. Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease. Vaccine, 33 (5), pp. 726-733.
Cichon, A.-C. and Brown, D. R., 2014. Nrf-2 regulation of prion protein expression is independent of oxidative stress. Molecular and Cellular Neuroscience, 63, pp. 31-37.
Walsh, K. P., Minamide, L. S., Kane, S. J., Shaw, A. E., Brown, D. R., Pulford, B., Zabel, M. D., Lambeth, J. D., Kuhn, T. B. and Bamburg, J. R., 2014. Amyloid-β and proinflammatory cytokines utilize a prion protein-dependent pathway to activate NADPH oxidase and induce cofilin-actin rods in hippocampal neurons. PLoS ONE, 9 (4), e95995.
Wright, J. A., Mchugh, P. C., Pan, S., Cunningham, A. and Brown, D. R., 2013. Counter-regulation of alpha- and beta-synuclein expression at the transcriptional level. Molecular and Cellular Neuroscience, 57, pp. 33-41.
Younan, N.D., Sarell, C.J., Davies, P., Brown, D.R. and Viles, J.H., 2013. The cellular prion protein traps Alzheimer's Aβ in an oligomeric form and disassembles amyloid fibers. FASEB Journal, 27 (5), pp. 1847-1858.
McHugh, P. C., Wright, J. A., Williams, R. J. and Brown, D. R., 2012. Prion protein expression alters APP cleavage without interaction with BACE-1. Neurochemistry International, 61 (5), pp. 672-680.
Younan, N.D., Nadal, R.C., Davies, P., Brown, D. R. and Viles, J.H., 2012. Methionine oxidation perturbs the structural core of the prion protein and suggests a generic misfolding pathway. Journal of Biological Chemistry, 287 (34), pp. 28263-28275.
Meloni, G., Crameri, A., Fritz, G., Davies, P., Brown, D. R., Kroneck, P. M. H. and Vašák, M., 2012. The catalytic redox activity of prion protein-cuII is controlled by metal exchange with the ZnII-Thiolate clusters of Zn7Metallothionein-3. ChemBiochem, 13 (9), pp. 1261-1265.
Hesketh, S., Thompsett, A. R. and Brown, D. R., 2012. Prion protein polymerisation triggered by manganese-generated prion protein seeds. Journal of Neurochemistry, 120 (1), pp. 177-189.
Wojtera, M., Sobów, T., Kłoszewska, I., Liberski, P. P., Brown, D. R. and Sikorska, B., 2012. Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer's disease:Morphometric study and review of the literature. Folia Neuropathologica, 50 (1), pp. 74-84.
Mot, A. I., Wedd, A. G., Sinclair, L., Brown, D. R., Collins, S. J. and Brazier, M. W., 2011. Metal attenuating therapies in neurodegenerative disease. Expert Review of Neurotherapeutics, 11 (12), pp. 1717-1745.
Younan, N. D., Klewpatinond, M., Davies, P., Ruban, A. V., Brown, D. R. and Viles, J. H., 2011. Copper(II)-Induced Secondary Structure Changes and Reduced Folding Stability of the Prion Protein. Journal of Molecular Biology, 410 (3), pp. 369-382.
Davies, P., Wang, X. Y., Sarell, C. J., Drewett, A., Marken, F., Viles, J. H. and Brown, D. R., 2011. The synucleins are a family of redox-active copper binding proteins. Biochemistry, 50 (1), pp. 37-47.
McHugh, P. C., Wright, J. A. and Brown, D. R., 2011. Transcriptional regulation of the beta-synuclein 5 '-promoter metal response element by metal transcription factor-1. PLoS ONE, 6 (2), e17354.
Wang, X., Moualla, D., Wright, J. A. and Brown, D. R., 2010. Copper binding regulates intracellular alpha-synuclein localisation, aggregation and toxicity. Journal of Neurochemistry, 113 (3), pp. 704-714.
Brown, D. R., 2010. Oligomeric alpha-synuclein and its role in neuronal death. IUBMB Life, 62 (5), pp. 334-339.
Wang, X. and Brown, D. R., 2010. Synuclein proteins and their roles as metal binding proteins. In: Huang, S., ed. Metals and Neurodegeneration. Research Signpost, pp. 177-210.
Wright, J. A., Mchugh, P. C., Stockbridge, M., Lane, S., Kralovicova, S. and Brown, D. R., 2009. Activation and repression of prion protein expression by key regions of intron 1. Cellular and Molecular Life Sciences (CMLS), 66 (23), pp. 3809-3820.
Davies, P. and Brown, D. R., 2009. Manganese enhances prion protein survival in model soils and increases prion infectivity to cells. PLoS ONE, 4 (10), e7518.
Brown, D. R., 2009. Role of microglia in age-related changes to the nervous system. TheScientificWorldJOURNAL, 9, pp. 1061-1071.
Nadal, R. C., Davies, P., Brown, D. R. and Viles, J. H., 2009. Evaluation of Copper(2+) Affinities for the Prion Protein. Biochemistry, 48 (38), pp. 8929-8931.
Wright, J. A., Wang, X. and Brown, D. R., 2009. Unique copper-induced oligomers mediate alpha-synuclein toxicity. FASEB Journal, 23 (8), pp. 2384-2393.
Madine, J., Wang, X., Brown, D. R. and Middleton, D. A., 2009. Evaluation of β-Alanine- and GABA-substituted peptides as inhibitors of disease-linked protein aggregation. ChemBiochem, 10 (12), pp. 1982-1987.
Brown, D. R., 2009. Gene regulation as a potential avenue for the treatment of neurodegenerative disorders. Expert Opinion on Drug Discovery, 4 (5), pp. 515-524.
Brown, D. R., 2009. Brain proteins that mind metals: a neurodegenerative perspective. Dalton Transactions, 21, pp. 4069-4076.
O'Sullivan, D. B. D., Jones, C. E., Abdelraheim, S., Brazier, M. W., Toms, H., Brown, D. R. and Viles, J. H., 2009. Dynamics of a truncated prion protein, PrP(113-231), from 15N NMR relaxation: Order parameters calculated and slow conformational fluctuations localized to a distinct region. Protein Science, 18 (2), pp. 410-423.
Stevens, D. J., Walter, E. D., Rodriguez, A., Draper, D., Davies, P., Brown, D. R. and Millhauser, G. L., 2009. Early Onset Prion Disease from Octarepeat Expansion Correlates with Copper Binding Properties. PLoS Pathogens, 5 (4), e1000390.
Brown, D. R., 2009. Metal binding to alpha-synuclein peptides and its contribution to toxicity. Biochemical and Biophysical Research Communications, 380 (2), pp. 377-381.
Chang, B. G., Gray, P., Piltch, M., Bulgin, M. S., Sorensen-Melson, S., Miller, M. W., Davies, P., Brown, D. R., Coughlin, D. R. and Rubenstein, R., 2009. Surround optical fiber immunoassay (SOFIA): An ultra-sensitive assay for prion protein detection. Journal of Virological Methods, 159 (1), pp. 15-22.
Kralovicova, S., Fontaine, S. N., Alderton, A., Alderman, J., Ragnarsdottir, K. V., Collins, S. J. and Brown, D. R., 2009. The effects of prion protein expression on metal metabolism. Molecular and Cellular Neuroscience, 41 (2), pp. 135-147.
Davies, P., Marken, F., Salter, S. and Brown, D. R., 2009. Thermodynamic and Voltammetric Characterization of the Metal Binding to the Prion Protein: Insights into pH Dependence and Redox Chemistry. Biochemistry, 48 (12), pp. 2610-2619.
Sellarajah, S., Boussard, C., Lekishvili, T., Brown, D. R. and Gilbert, I. H., 2008. Synthesis and testing of peptides for anti-prion activity. European Journal of Medicinal Chemistry, 43 (11), pp. 2418-2427.
Büchl, A., Hawkesworth, C., Ragnarsdottir, K. V. and Brown, D. R., 2008. Re-partitioning of Cu and Zn isotopes by modified protein expression. Geochemical Transactions, 9 (11).
Uppington, K. M. and Brown, D. R., 2008. Resistance of cell lines to prion toxicity aided by phospho-ERK expression. Journal of Neurochemistry, 105 (3), pp. 842-852.
Hesketh, S., Sassoon, J., Knight, R. and Brown, D. R., 2008. Elevated manganese levels in blood and CNS in human prion disease. Molecular and Cellular Neuroscience, 37 (3), pp. 590-598.
Zhu, F., Davies, P., Thompsett, A. R., Kelly, S. M., Tranter, G. E., Hecht, L., Isaacs, N. W., Brown, D. R. and Barron, L. D., 2008. Raman optical activity and circular dichroism reveal dramatic differences in the influence of divalent copper and manganese ions on prion protein folding. Biochemistry, 47 (8), pp. 2510-2517.
Wright, J. A. and Brown, D. R., 2008. Alpha-synuclein and its role in metal binding: Relevance to Parkinson's disease. Journal of Neuroscience Research, 86 (3), pp. 496-503.
Davies, P., Fontaine, S. N., Moualla, D., Wang, X. Y., Wright, J. A. and Brown, D. R., 2008. Amyloidogenic metal-binding proteins: new investigative pathways. Biochemical Society Transactions, 36, pp. 1299-1303.
Liberski, P. P., Brown, D. R., Sikorska, B., Caughey, B. and Brown, P., 2008. Cell death and autophagy in prion diseases (transmissible spongiform encephalopathies). Folia Neuropathologica, 46 (1), pp. 1-25.
Klewpatinond, M., Davies, P., Bowen, S., Brown, D. R. and Viles, J. H., 2008. Deconvoluting the Cu2+ binding modes of full-length prion protein. Journal of Biological Chemistry, 283 (4), pp. 1870-1881.
Goni, F., Prelli, F., Schreiber, F., Scholtzova, H., Chung, E., Kascsak, R., Brown, D. R., Sigurdsson, E. M., Chabalgoity, J. A. and Wisniewski, T., 2008. High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience, 153 (3), pp. 679-686.
Haigh, C. L. and Brown, D. R., 2008. Investigation of PrPC Metabolism and Function in Live Cells. Methods in Molecular Biology, 459, pp. 21-34.
Brown, D. R., 2008. Prions and trace elements. In: Schlegel, P., Durosoy, S. and Jongbloed, A. W., eds. Trace elements in animal production systems OTEANE. Wageningen, Netherlands: Wageningen Academic Publishers, pp. 231-242.
Davies, P. and Brown, D. R., 2008. The chemistry of copper binding to PrP: is there sufficient evidence to elucidate a role for copper in protein function? Biochemical Journal, 410, pp. 237-244.