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.

A list of publications is available from the institutional repository, SHURA

ILLES-TOTH, E, RAMOS, MR, CAPPAI, R, DALTON, CF and SMITH, DP (2015). Structural characterisation of oligomeric alpha-synuclein by ion mobility spectrometry mass spectrometry. Biochem J.(doi:10.1042/BJ20150159)

KRIECHBAUMER, V, NABOK, A, MUSTAFA, MK, AL-AMMAR, R, SMITH, DP, ABELL, BM (2011) Biophysical analysis of receptor protein interactions observed in situ on native chloroplast membranes via total internal reflection ellipsometry. PLoS One. 2012;7(3):e34455. Epub 2012 Mar 29.

SMITH, DP, WOODS, LA, RADFORD, SE, ASHCROFT, AE (2011). Structure and dynamics of oligomeric intermediates in β2-microglobulin self-assembly. Biophysical Journal

TEW, DJ, BOTTOMLEY, SP, SMITH, DP, CICCOTOSTO, GD, BABON, J, HINDS, MG, MASTERS, CL, CAPPAI, R, BARNHAM, KJ (2007). Stabilization of neurotoxic soluble β-sheet-rich conformations of the Alzheimer’s disease Amyloid-β peptide. Biophys. J. 94(7): 2752-2766

SMITH, DP, GILES, K, BATEMAN, RH, RADFORD, SE, ASHCROFT, AE, (2007). Monitoring co-populated conformational states during protein folding events using electrospray ionisation - ion mobility spectrometry- mass spectrometry. J.A.S.M.S. 18(12):2180-2190
Awarded the Ronald A. Hites Award for Outstanding Research Publication by the American Society for Mass Spectrometry

FODERO-TAVOLETTI, MT, SMITH, DP, MCLEAN, CA, ADLARD, PA, BARNHAM, KJ, FOSTER, LE, LEONE L, CORTES, M, CULVENOR, JG, LI, Q. LAUGHTON, KM, ROWE, CC, MASTERS, CL, CAPPAI, R, VILLEMAGNE, VL (2007). In vitro characterisation of Pittsburgh Compound-B (PIB) binding to Lewy Bodies. J. Neurosci. 27(39):10365-10371.

SMITH, DP, CICCOTOSTO, GD, TEW, DJ, FODERO-TAVOLETTI, MT, JOHANSSEN, T, MASTERS, CL, BARNHAM, KJ, CAPPAI, R (2007). Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer’s disease Amyloid-β peptide. Biochemistry 46 (10): 2881-2891

DUCE, JA, SMITH, DP, BLAKE, R, CAPPAI, R, MASTERS, CL, TROUNCE, I (2006). Linker Histone H1 binds to disease associated amyloid-like fibrils. Journal of Molecular Biology 361:493-505

SMITH, DP, SMITH, DG, CICCOTOSTO, GD, CURTAIN, CC, LAU, TL, BOAS, JF, TEW, DJ, PEREZ, K, PILBROW, JR, WADE, JD, DREW, SC, SEPAROVIC, F, MASTERS, CL, CAPPAI, R, BARNHAM, KJ (2006). Cu2+-Amyloid β mediated toxicity depends on an intermolecular histidine bridge. Journal of Biological Chemistry 281:15145-15154

CAPPAI, R, LECK, S, TEW, DJ, WILLIAMSON, NA, SMITH, DP, GALATIS, D, SHARPLES, RA, CURTAIN, CC, ALI, FE, CHERNY, RA, CULVENOR, JG, BOTTOMLEY, SP, MASTERS, CL, BARNHAM, KJ, HILL, AF (2005). Dopamine promotes α-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB Journal 10:1377-9

SMITH, DP, JONES, S, SUNDE, M, SERPELL, L, RADFORD, SE (2003). A systematic investigation into the effect of protein destabilisation on beta-2-microglobulin amyloid formation. Journal of Molecular Biology 330:943-954

JONES, S, SMITH, DP, RADFORD, SE (2003). Role of the N- and C-terminal strands of beta-2-microglobulin in amyloid formation at neutral pH. Journal of Molecular Biology 330:935-941

KAD, NM, MYERS, SL, SMITH, DP, SMITH, DA, RADFORD, SE, THOMSON, NH (2003). Hierarchical assembly of beta-2-microglobulin amyloid in vitro revealed by atomic force microscopy. Journal of Molecular Biology 330:785-797

TRINH, C*, SMITH, DP*, KALVERDA, AP, PHILLIPS, SEV, RADFORD, SE (2002). Crystal structure of human monomeric beta-2-microglobulin reveals clues to its amyloidogenic properties. Proceedings of the National Academy of Sciences of the United States of America 99:9771-9776
* Joint First Author

KAD, NM, THOMPSON, NH, SMITH, DP, SMITH, DA, 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 313:559-571

SMITH, DP, RADFORD, SE (2001). Role of the single disulphide bond of beta-2-microglobulin in amyloidosis in vitro. Protein Science 10:1775-1784

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.