RESEARCH PROFILE

An increasing number of diseases are associated with misfolding of proteins, which can lead to the acummulation in vital organs of amorphous protein aggregates or ordered amyloid fibrils. These diseases include conditions such as Alzheimer's, Huntington's, Parkinson's and transmissible spongiform encephalopathies (TSEs). TSEs, such as mad cow disease in cattle, scrapie in sheep, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS) and fatal familial insomnia (FFI) in humans, are associated with the conversion of a cellular plasma membrane glycoprotein, the prion protein, to an altered form that is suggested to be both the infectious agent and the cause of rapid neurodegeneration. Structural studies have established that prion conversion from the cellular healthy conformation to the disease-associated form involves a major refolding of the prion protein that results in amorphous aggregates or ordered amyloid fibrils.

In my research group we are interested in understanding the molecular mechanism of prion conversion, studying the folding and structure of prions both in solution and in association with lipid membranes, the aggregation and fibrillization of prions, and the mechanisms of neurodegeneration and neuronal death.

RESEARCH PROJECTS

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SELECTED PUBLICATIONS

• Graham, J.F., Kurian, D., Argarwal, S., Toovey, L., Hunt, L., Kirby, L., Pinheiro, T. J. T., Banner, S.J. and Gill, A. C.(2012) 'Na+/K+-ATPase is present in scrapie-associated fibrils, modulates PrP misfolding in vitro and links PrP function and dysfunction' PLoS One 6 (11), 26813 (1932-6203)
• Lu, J., Stewart, A.J., Sleep, S., Sadler, P.J., Pinheiro, T.J.T and Blindaeur, C.A.(2012) 'A molecular mechanism for modulating plasma Zn speciation by fatty acids.' Journal Of American Chemical Society 134 (3), 1454 - 1457 (0002-7863)
• Sanghera, N., Correia, E.F.S., Correia, J.R.S., Ludwig, L., Nakamura H. K., Kuwata, K., Samain, E. Gill, A. C., Pinheiro, T.J.T.(2011) 'Deciphering the molecular details for the binding of the prion protein to main ganglioside GM1 of neuronal membranes' Chemistry & Biology (18), 1422 - 1431 (1074-5521)
• Monteiro, J. P., Martins, A. F., Lúcio, M., et al.(2011) 'Nimesulide interaction with membrane model systems : are membrane physical effects involved in nimesulide mitochondrial toxicity?' Toxicology in Vitro 25 (6), 1215 - 1223 (0887-2333) [article]
• Andrew C. Gill, Sonya Agarwal, Teresa J.T. Pinheiro and James F. Graham(2010) 'Structural requirements for efficient prion protein conversion: Cofactors may promote a conversion-competent structure for PrPC ' 4 (4), 235 - 242

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