Dr David P Smith NTF, BSc, PhD, SFHEA

David is a National Teaching Fellow of the Higher Education Academy and has been awarded the Sheffield Hallam Vice Chancellor's Award for Inspirational Teaching. His research interests bring together protein chemistry, cell culture and mass spectrometry to investigate the molecular basis of Parkinson's disease. This research is applied directly to his teaching giving context and authenticity, an approach that has been recognised through the nomination of the University Inspirational Teaching Award to the maximum of three times and faculty award seven times.

David is passionate about disseminating and enhancing teaching practises. He has worked directly with bioscientists and other academics across multiple institutions on teaching enhancements and delivers invited workshops and conference presentations on student engagement. He has developed the pedagogical theory of object-based learning through the use of 3D-printed biological molecules, producing digital tool kits to disseminate this practice. He has also integrated various forms of technology enhanced learning into the practice of the department from the use of Padlet for student support, collaborative learning tools to facilitate interaction and lecture flipping technologies.

Specialist areas of interest

Biochemistry / Biotechnology
Ion Mobility Spectrometry - Mass Spectrometry
Protein Chemistry
Amyloid formation
Teaching Innovations

David teaches core biochemistry and the molecular biosciences and is currently course leader for MSc Molecular and Cellular Biology.

David's research is focussed on understanding the structure and function of amyloid oligomers thought to be responsible for cell death in Parkinson's disease.

Parkinson's disease (PD)

PD occurs in 0.17% of the general population affecting ~1 to 2 per cent of those over 80 years old. Although rare heritable forms of PD have been documented, the sporadic form is far more common and this is possibly connected to environmental factors. The molecular mechanisms of neurodegeneration in PD are mostly unknown and the lack of preventative treatments for PD is undoubtedly a result of our limited understanding of the underlying aetiology. A critical step is the formation of metal rich Lewy bodies, in which alpha-synuclein in the form of amyloid-like aggregates has been identified as a major component. Soluble alpha-synuclein oligomers populated during amyloid assembly have been implicated as the causative agent in PD. David's group is developing novel 3D cell culture systems to investigate the molecular basis of the Lewy body formation brought about by exposure to metals and these oligomers.

Ion mobility mass spectrometry of non-covalent complexes

Detailed knowledge of the tertiary and quaternary structure of proteins and protein complexes is of immense importance in understanding their functionality. To investigate this, David carries out research using electrospray ionisation - ion mobility spectrometry - mass spectrometry (ESI-IMS-MS). This is an analytical technique used to characterise the conformational states of monomeric proteins and large non-covalent complexes such as amyloid oligomers. ESI-IMS-MS is used to assess the size (molecular weight) and shape distribution (CCS) of the oligomers and any covalent modification to the protein. By comparison with models, estimates of the degree of compactness and general shape adopted by the oligomers is possible. Through this work the structural and conformation of differing forms of alpha-synuclein oligomers as well as the effect of phosphorylation and metal binding is being addressed. The results gained raise the possibility of intervention via small molecule inhibition, as differences between toxic and non-toxic oligomeric forms are identified.

Journal articles

Taylor-Whiteley, T.R., Le Maitre, C.L., Duce, J.A., Dalton, C.F., & Smith, D.P. (2019). Recapitulating Parkinson's disease pathology in a three-dimensional human neural cell culture model. Disease Models & Mechanisms, 12 (4). http://doi.org/10.1242/dmm.038042

Hogeling, S.M., Cox, M., Bradshaw, R., Smith, D., & Duckett, C.J. (2019). Quantification of proteins in whole blood, plasma and DBS, with element-labelled antibody detection by ICP-MS. Analytical biochemistry, 575, 10-16. http://doi.org/10.1016/j.ab.2019.03.006

Smith, D. (2018). Evidencing your lifelong learning with e-Portfolio. Biochemist, 40 (5), 22-24.

Smith, D., Hoare, A., & Lacey, M. (2018). Who goes where? The importance of peer groups on attainment and the student use of the lecture theatre teaching space. FEBS Open Bio, 8 (9), 1368-1378. http://doi.org/10.1002/2211-5463.12494

Duce, J., Wong, B., Durham, H., Devedjian, J.-.C., Smith, D., & Devos, D. (2017). Post translational changes to α-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson's disease. Molecular neurodegeneration, 12 (45), 1-12. http://doi.org/10.1186/s13024-017-0186-8

Mason, R., Paskins, A., Dalton, C., & Smith, D. (2016). Copper Binding and Subsequent Aggregation of α-Synuclein Are Modulated by N-Terminal Acetylation and Ablated by the H50Q Missense Mutation. Biochemistry, 55 (34), 4737-4741. http://doi.org/10.1021/acs.biochem.6b00708

Smith, D.P. (2016). Active learning in the lecture theatre using 3D printed objects. F1000Research, 5 (61), 1-18. http://doi.org/10.12688/f1000research.7632.2

Harvey, A., Day, R., Cole, L.M., Bartlett, M., Warwick, J., Bojar, R., ... Clench, M.R. (2016). MALDI-MSI for the analysis of a 3D tissue-engineered psoriatic skin model. Proteomics, 16 (11-12), 1718-1725. http://doi.org/10.1002/pmic.201600036

Smith, D.P. (2016). Bringing experiential learning into the lecture theatre using 3D printed objects [version 1; referees: 2 approved with reservations]. F1000Research, 5. http://doi.org/10.12688/F1000RESEARCH.7632.1

Leonenko, Z., Smith, R.A.S., Nabok, A., Blakeman, B.J.F., Xue, W.-.F., Abell, B., & Smith, D.P. (2015). Analysis of toxic amyloid fibril interactions at natively derived membranes by ellipsometry. PLOS ONE, 10 (7), e0132309. http://doi.org/10.1371/journal.pone.0132309

Greggio, E., Leong, S.L., Hinds, M.G., Connor, A.R., Smith, D., Illes-Toth, E., ... Cappai, R. (2015). The N-Terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation. PLoS ONE, 10 (2), e0116497. http://doi.org/10.1371/journal.pone.0116497

Illes-toth, E., Ramos, M., Cappai, R., Dalton, C., & Smith, D. (2015). Distinct higher-order alpha-synuclein oligomers induce intracellular aggretation. Biochemical Journal, 468 (3), 485-493. http://doi.org/10.1042/BJ20150159

Illes-Toth, E., Dalton, C.F., & Smith, D. (2013). Binding of Dopamine to Alpha-Synuclein is Mediated by Specific Conformational States. Journal of The American Society for Mass Spectrometry, 24 (9), 1346-1354. http://doi.org/10.1007/s13361-013-0676-z

Illes-Toth, E., & Smith, D. (2013). Conformations and Assembly of Amyloid Oligomers by Electrospray Ionisation - Ion Mobility Spectrometry - Mass Spectrometry. Current Analytical Chemistry, 9 (2), 165-180. http://doi.org/10.2174/157341113805218992

Cole, L.M., Mahmoud, K., Haywood-Small, S., Tozer, G.M., Smith, D.P., & Clench, M.R. (2013). Recombinant "IMS TAG" proteins - A new method for validating bottom-up matrix-assisted laser desorption/ionisation ion mobility separation mass spectrometry imaging. Rapid Communications in Mass Spectrometry, 27 (21), 2355-2362. http://doi.org/10.1002/rcm.6693

Kriechbaumer, V., Nabok, A., Widdowson, R., Smith, D., & Abell, B. (2012). Quantification of ligand binding to g-protein coupled receptors on cell membranes by ellipsometry. PLoS ONE, 7 (9), e46221.

Kriechbaumer, V., Nabok, A., Mustafa, M., Al-Ammar, R., Tsargorodskaya, A., Smith, D., & Abell, B. (2012). Analysis of protein interactions at native chloroplast membranes by ellipsometry. PLoS ONE, 7 (3), e34455. http://doi.org/10.1371/journal.pone.0034455

Smith, D., Woods, L.A., Radford, S.E., & Ashcroft, A.E. (2011). Structure and dynamics of oligomeric intermediates in β2-microglobulin self-assembly. Biophysical Journal, 101 (5), 1238-1247. http://doi.org/10.1016/j.bpj.2011.07.023

Kriechbaumer, V., Tsargorodskaya, A., Mustafa, M., Vinogradova, T., Lacey, J., Smith, D., ... Nabok, A. (2011). Study of receptor-chaperone interactions using the optical technique of spectroscopic ellipsometry. Biophysical Journal, 101 (2), 504-511. http://doi.org/10.1016/j.bpj.2011.06.011

Smith, D.P., Radford, S.E., & Ashcroft, A.E. (2010). Elongated oligomers in β2-microglobulin amyloid assembly revealed by ion mobility spectrometry-mass spectrometry. Proceedings of the National Academy of Sciences, 107 (15), 6794-6798. http://doi.org/10.1073/pnas.0913046107

Ladner, C.L., Chen, M., Smith, D., Platt, G.W., Radford, S.E., & Langen, R. (2010). Stacked sets of parallel, in register beta-strands of beta-2-microglobulin in amyloid fibrils revealed by site-directed spin labelling and chemical labelling. Journal of Biological Chemistry, 285 (22), 17137-17147. http://doi.org/10.1074/jbc.M110.117234

Knapman, T., Smith, D., Campuzano, I., Malham, R., Berryman, J., Radford, S., & Ashcroft, A. (2009). Deciphering drift time measurements from travelling wave ion mobility spectrometry-mass spectrometry studies. European Journal of Mass Spectrometry, 15 (5), 113. http://doi.org/10.1255/ejms.947

Smith, D.P., Anderson, J., Plante, J., Ashcroft, A.E., Radford, S.E., Wilson, A.J., & Parker, M.J. (2008). Trifluoromethyldiazirine : an effective photo-induced cross-linking probe for exploring amyloid formation. Chemical Communications, (44), 5728. http://doi.org/10.1039/B813504E

Barnham, K.J., Kenche, V.B., Ciccotosto, G.D., Smith, D.P., Tew, D.J., Liu, X., ... Cappai, R. (2008). Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease. Proceedings of the National Academy of Sciences, 105 (19), 6813-6818. http://doi.org/10.1073/pnas.0800712105

Giannakis, E., Pacifico, J., Smith, D.P., Hung, L.W., Masters, C.L., Cappai, R., ... Barnham, K.J. (2008). Dimeric structures of α-synuclein bind preferentially to lipid membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1778 (4), 1112-1119. http://doi.org/10.1016/j.bbamem.2008.01.012

Smith, D.P., Tew, D.J., Hill, A.F., Bottomley, S.P., Masters, C.L., Barnham, K.J., & Cappai, R. (2008). Formation of a high affinity lipid-binding intermediate during the early aggregation phase of α-synuclein. Biochemistry, 47 (5), 1425-1434. http://doi.org/10.1021/bi701522m

Tew, D.J., Bottomley, S.P., Smith, D.P., Ciccotosto, G.D., Babon, J., Hinds, M.G., ... Barnham, K.J. (2008). Stabilization of neurotoxic soluble beta-sheet-rich conformations of the Alzheimer's disease amyloid-beta peptide. Biophysical journal, 94 (7), 2752-2766. http://doi.org/10.1529/biophysj.107.119909

Smith, D.P., Giles, K., Bateman, R.H., Radford, S.E., & Ashcroft, A.E. (2007). Monitoring copopulated conformational states during protein folding events using electrospray ionization-ion mobility spectrometry-mass spectrometry. Journal of The American Society for Mass Spectrometry, 18 (12), 2180-2190. http://doi.org/10.1016/j.jasms.2007.09.017

Fodero-Tavoletti, M.T., Smith, D.P., McLean, C.A., Adlard, P.A., Barnham, K.J., Foster, L.E., ... Villemagne, V.L. (2007). In vitro characterization of Pittsburgh compound-B binding to Lewy bodies. The Journal of Neuroscience, 27 (39), 10365-10371. http://doi.org/10.1523/JNEUROSCI.0630-07.2007

Smith, D.P., Ciccotosto, G.D., Tew, D.J., Fodero-Tavoletti, M.T., Johanssen, T., Masters, C.L., ... Cappai, R. (2007). Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer's disease amyloid-beta peptide. Biochemistry, 46 (10), 2881-2891. http://doi.org/10.1021/bi0620961

Smith, D.P., Smith, D.G., Curtain, C.C., Boas, J.F., Pilbrow, J.R., Ciccotosto, G.D., ... Barnham, K.J. (2006). Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge. JOURNAL OF BIOLOGICAL CHEMISTRY, 281 (22), 15145-15154. http://doi.org/10.1074/jbc.M600417200

Cappai, R., Leck, S.L., Tew, D.J., Williamson, N.A., Smith, D.P., Galatis, D., ... Hill, A.F. (2005). Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB JOURNAL, 19 (8), 1377-+. http://doi.org/10.1096/fj.04-3437fje

Jones, S., Smith, D.P., & Radford, S.E. (2003). Role of the N and C-terminal strands of beta 2-microglobulin in amyloid formation at neutral pH. JOURNAL OF MOLECULAR BIOLOGY, 330 (5), 935-941. http://doi.org/10.1016/S0022-2836(03)00688-0

Smith, D.P., Jones, S., Serpell, L.C., Sunde, M., & Radford, S.E. (2003). A systematic investigation into the effect of protein destabilisation on beta 2-microglobulin amyloid formation. JOURNAL OF MOLECULAR BIOLOGY, 330 (5), 943-954. http://doi.org/10.1016/S0022-2836(03)00687-9

Kad, N.M., Myers, S.L., Smith, D.P., Smith, D.A., Radford, S.E., & Thomson, N.H. (2003). Hierarchical assembly of beta(2)-microglobulin amyloid in vitro revealed by atomic force microscopy. JOURNAL OF MOLECULAR BIOLOGY, 330 (4), 785-797. http://doi.org/10.1016/S0022-2836(03)00583-7

Trinh, C.H., Smith, D.P., Kalverda, A.P., Phillips, S.E.V., & Radford, S.E. (2002). Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 99 (15), 9771-9776. http://doi.org/10.1073/pnas.152337399

Kad, N.M., Thomson, N.H., Smith, D.P., Smith, D.A., & Radford, S.E. (2001). beta(2)-microglobulin and its deamidated variant, N17D form amyloid fibrils with a range of morphologies in vitro. JOURNAL OF MOLECULAR BIOLOGY, 313 (3), 559-571. http://doi.org/10.1006/jmbi.2001.5071

Smith, D.P., & Radford, S.E. (2001). Role of the single disulphide bond of beta(2)-microglobulin in amyloidosis in vitro. PROTEIN SCIENCE, 10 (9), 1775-1784. http://doi.org/10.1110/ps.4901

Conference papers

Paskins, A.R., Dalton, C.F., Duckett, C.J., & Smith, D.P. (2016). INVESTIGATING METAL BINDING AND THE RESULTING CONFORMATIONAL CHANGES AND AGGREGATION OF MONOMERIC WILD-TYPE ALPHA-SYNUCLEIN AND A PHOSPHORYLATION MIMIC. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 36, 594-595.

Book chapters

Giannakis, E., Hung, L.-.W., Camacaro, K.P., Smith, D., Barnham, K., & Wade, J.D. (2008). Analysis of Aβ interactions using ProteinChip Technology. In Otvos, L. (Ed.) Peptide-based drug design. (pp. 71-86). Humana Press: http://doi.org/10.1007/978-1-59745-419-3_5

Theses / Dissertations

Mason, R. (2018). Conformational changes and the self-assembly of alpha-synuclein. (Doctoral thesis). Supervised by Smith, D. http://doi.org/10.7190/shu-thesis-00151

Paskins, A.R. (2017). Aggregation and conformation of alpha-synuclein: effects of ligand binding and phosphomimetics. (Doctoral thesis). Supervised by Smith, D. http://doi.org/10.7190/shu-thesis-00071

Smith, R.A.-.S. (2015). Detection of protein interactions at cellular membranes using total internal reflection ellipsometry. (Doctoral thesis). Supervised by Abell, B., & Smith, D.

Illes-Toth, T.E. (2013). Linking the structure of alpha-synuclein oligmers to function in Parkinson's disease. (Doctoral thesis). Supervised by Smith, D., & Dalton, C.

Previous supervision:

Teresa Whiteley - Recapitulating Parkinson's disease pathology in a 3D neural cell culture model

Becky Mason - Investigating the dynamics and assembly of alpha-synuclein amyloid oligomers by electrospray ionisation-ion mobility-mass spectrometry

Aimee Paskins - Metal homeostasis, phosphorylation and the effect on the aggregation of α-synuclein

David is particularly interested in how proteins, the molecular machines within the brain, change their shape and come together, creating neuro-degenerative diseases such as Alzheimer's disease and Parkinson's disease. Current research interests are centred on linking the structure of complexes to their toxic of function.