Professor David Allsop
Professor of Neuroscience
Office C38
Division of Biomedical and Life Sciences
Faculty of Health and Medicine
Lancaster University
Lancaster
LA1 4YQ
UK
Tel: +44 1524 592122
Fax: +44 1524 593192
E-mail: d.allsop@lancaster.ac.uk
Introduction
The formation of fibrillar aggregates from a range of different proteins is a common feature of numerous different 'protein conformational' diseases. In these diseases, normally soluble proteins are deposited in the form of insoluble fibrils inside and/or outside of cells. In the systemic amyloidoses, extracellular fibrillar deposits (often called amyloid) can be found in many different tissues and organs throughout the body. Localised deposits are found in some other diseases, such as late-onset diabetes, where they are restricted to the pancreas, and some important neurodegenerative diseases, where they are often found only in the brain. Examples of the latter include Alzheimer's disease, Parkinson's disease, the prion diseases (e.g. CJD in humans), Huntington's disease, frontotemporal dementia and motor neuron disease. My research is concerned with the pathological role of these misfolded proteins, and is focussed mainly on neurodegenerative disease and late-onset (type 2) diabetes.
Research Interests
There are three major aspects to my research:
1. Mechanism of amyloid toxicity
My research group are studying the potential mechanisms by which the accumulation of protein aggregates can lead to cellular degeneration and loss. We have discovered that the aggregating proteins implicated in Alzheimer's disease, Parkinson's disease, prion disease and late-onset diabetes all have the common ability to generate hydrogen peroxide and, subsequently, hydroxyl free radicals. The proteins involved all appear to do this through key interactions with redox-active transition metal ions, particularly those of iron and copper. Our current hypothesis is that tissue damage caused by the formation of these types of 'reactive oxygen species' could be a common mechanism of cell death in several different protein misfolding disorders.
I have recently organised a Biochemical Society Focus Meeting on metals and brain disease.
Our current research in this area is supported by The Alzheimer's Society.
2. Amyloid proteins as disease biomarkers
A further aspect of my research is the detection of early protein aggregates, sometimes called soluble oligomers, in body fluids (cerebrospinal fluid and blood) as potential biomarkers for disease. There are two main aspects to this work:
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The development of improved diagnostic markers, to allow early detection and consequently improved treatment of disease
The development of molecular markers to enable the tracking of disease progression in already diagnosed patients - this would help to streamline drug testing in clinical trials
Our current research in this area is focussed mainly on two molecular markers called α-synuclein (associated with Parkinson's disease and related disorders) and TDP 43 (associated with motor neuron disease and frontotemporal dementia). We were the first research group to detect the presence of each of these proteins in human blood plasma. Currently we are studying longitudinal changes in α-synuclein in Parkinson's disease (supported by MRC) and we are also part of large European Community (Framework 6) Project called NEUROSCREEN on the development of a multiplex system for simultaneous assay of multiple biomarkers related to neurodegenerative disease. We are also studying biomarkers in motor neuron disease (supported by The George Barton Trust).
3. Amyloid inhibitors as novel therapeutics
Blocking the formation of early toxic protein aggregates, or interfering with their ability to generate reactive oxygen species, could be a novel approach to the treatment of some protein misfolding diseases. We have recently published two research papers on peptide-based aggregation inhibitors that could ultimately provide a new treatment for Alzheimer's disease and Parkinson's disease. Also, we have a very active collaboration with a biotechnology company called 'Zapaloid' on the clinical development of a similar type of new approach for the treatment of Parkinson's disease, and are part of a European Community (Framework 7) Project based on the use of nanoparticles for the improved diagnosis and treatment of Alzheimer's disease. We also have long-term funding (joint with The Department of Psychology) from the Fisher Foundation to develop improved methods for the diagnosis and treatment of Alzheimer's disease.
Funding
My research is currently supported by The Medical Research Council, The European Commission, The Alzheimer's Society, The George Barton Trust, The Fisher Foundation, and Zapaloid, with total funding well in excess of £1,000,000.
Current members of my research team
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Dr. Susan Moore - PDRA
Dr. Mark Taylor - PDRA
Penny Foulds - PDRA
Jenny Mayes - Ph.D. Student
Lee Hayes - Ph.D. Student
Kirsty Humphreys - M.Sc.
Sophia Hou - M.Sc.
Dennis Ma - M.Sc.
Kath Lamb - technician
Prizes
Joint Winner of Commercialisation Prize (Lancaster University Staff Award), 2006
Teaching
BIOL 125: Human Physiology (Module Organiser)
BIOL 352: Biomedicine, Chronic Diseases (Module Organiser)
BIOL 436: Brain and Eye Disease (Module Organiser)
SSM4/SSM6: Special Study Modules for Medical Students on Protein Aggregation and Neurodegeneration.
External Appointments
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Member of Steering Committee for DeNDRoN North West
Regular Member and Chair of Grant Awarding Panel, The Alzheimer's Society
Member of Theme Panel VII (Development and Disease), The Biochemical Society
Member of Editorial Board of the journal Biologics: Targets and Therapy
Fellow of The Royal Society of Medicine
Selected Publications
El-Agnaf OMA, Salem SS, Paleologou KE, Gibson MJ, Curran MD, Court JA, Mann DMA, Ikeda SI, Cookson MR, Hardy J & Allsop D. (2003) α synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 17, 1945-1947. [Full Text]
El-Agnaf OMA, Paleologou KE, Greer B, Abogrein AM, King JE, Salem SA, Fullwood NJ, Benson FE, Hewitt R, Ford KJ, Martin FL, Harriott P, Cookson MR & Allsop D. (2004) A strategy for designing inhibitors of α-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders. FASEB J. 18, 1315-1317. [Full text]
Tabner BJ, El-Agnaf OMA, Turnbull S, German MJ, Paleologou KE, Hayashi Y, Cooper LJ, Fullwood NJ & Allsop D. (2005) Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer's disease and familial British dementia. J. Biol. Chem. 280, 35789-35792. [Full Text]
El-Agnaf OMA, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG & Allsop D. (2006) Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J. 20, 419-425. [Full Text]
Tokuda T., Salem S., Allsop D., Mizuno T., Nakagawa M., Qureshi M.M., Locascio J.J., Schlossmacher M.G. & El-Agnaf, O.M.A. (2006) Decreased α synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease. Biochem. Biophys. Res. Commun. 349, 162-166. [Pubmed]
Masad A., Hayes L., Tabner B.J, Turnbull S., Cooper L.J., Fullwood N.J., German M.J., Kametani F., El Agnaf O.M.A. & Allsop D. (2007) Copper-mediated formation of hydrogen peroxide from the amylin peptide: a novel mechanism for degeneration of islet cells in type-2 diabetes mellitus? FEBS Letts. 581, 3489-3493. [Pubmed]
Salem S.A., Allsop D., Mann D.M.A., Tokuda T. & El-Agnaf O.M.A. (2007) An investigation into the lipid binding properties of α-, β- and γ-synucleins in human brain and cerebrospinal fluid. Brain Res. 1170, 103-111. [Pubmed]
Foulds P., McAuley E., Gibbons L., Davidson Y., Pickering-Brown S.M., Neary D., Snowden J.S., Allsop D. & Mann D.M.A. (2008) TDP-43 protein can be detected in plasma in patients with Alzheimer’s disease and frontotemporal dementia and may witness the presence of TDP-43 pathology within the brain. Acta Neuropathol. 116, 141-146. [Pubmed]
Austen B.M., Paleologou K.E., Sumaya A., Ali E., Qureshi M.M., Allsop D. & El-Agnaf O.M.A. (2008) Designing peptide inhibitors for oligomerization and toxicity of Alzheimer’s β-amyloid peptide. Biochemistry 47, 1984-1992. [Pubmed]
Allsop D., Mayes J., Moore S., Masad A. & Tabner B. (2008) Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease. Biochem. Soc. Trans. 36, 1293-1298.[Pubmed]