Staniforth, Rosie, Dr

Dr Rosie Staniforth

School of Biosciences

Lecturer

r.a.staniforth@sheffield.ac.uk
+44 114 222 2761

Profile

2010 - present: Lecturer, University of ��«Ӱҵ
2001 - 2010: Royal Society University Research Fellow, University of ��«Ӱҵ
2000 - 2000: Wellcome Career Development Fellow University of ��«Ӱҵ
1997 - 2000: PDRA, Dept. Molecular Biology and Biotech., University of ��«Ӱҵ
1994 - 1997: Wellcome Trust Travelling Research Fellow to Europe, University of Rome “La Sapienza”, Italy
1994 - 1994: PDRA Dept. Biochemistry, University of Bristol

Research interests

Until very recently, our understanding of the causes behind neurodegenerative diseases has been very limited. The outbreak of BSE (commonly referred to as mad cow disease) and the rise of Alzheimer’s has meant that there is increasing pressure to obtain a cure. These two diseases are characterised by the accumulation of fibrous material called "amyloid" in the brain.

This substance has been shown to consist of naturally occurring proteins assembled into this unnatural mass. Whether or not this protein-based material is the direct cause for deterioration of brain tissue in patients suffering from these diseases is a matter of some controversy.

However, it is clear to all that these proteinaceous fibres are closely associated with the pathology: mutations in genes coding for these proteins cause the early onset of the disease and premature death. Another cause for hope is that this pattern of events may be common to almost all neurodegenerative diseases, including Parkinson’s and Huntington’s, and a large number of other diseases including certain forms of cancer, diabetes and stroke.

It is exciting to think that understanding the mechanism of amyloid formation may be a step towards a universal cure since, so far, therapies have only been targeted at alleviating symptoms but cannot prevent or halt the onset of these devastating diseases.

As a biochemist, my interest is in studying the assembly of "normal" proteins into amyloid fibres at a molecular level. A first consideration when tackling such a problem is that, unlike other polymers, protein molecules exist as unique three-dimensional structures in vivo (referred to as their folded state).

In amyloidogenesis, proteins with totally different folds form fibres with very similar properties suggesting there may be common, structurally analogous intermediates on the assembly route. This also means that considerable conformational changes (unfolding) of the protein molecules are likely to occur either before or after association.

A well-characterised protein with a number of advantageous properties is cystatin C, a protease inhibitor which is associated with a disease causing recurrent stroke (Human Cystatin C Amyloid Angiopathy).

I have identified a number of different conformers of this protein which could all be candidate precursors for the assembly process. These include partially folded states of the monomeric protein and a "domain-swapped" dimer.

The latter species is the result of two molecules of cystatin coming together and exchanging part of their chains by unfolding then refolding into a conformation made up of two cystatin-folds, where each protein chain contributes half its constituent amino acids to one fold and half to the other.

This is the first time this kind of intertwining of protein chains is observed for an amyloidotic protein. Such a process of assembly results in the formation of extremely stable oligomers and has often been speculated as a convenient mechanism for amyloid fibre formation.

Structural characterisation of the different forms of cystatin from monomer to dimer to fibre stretches the boundaries of current technology. We are using a combination of techniques including dynamic NMR (nuclear magnetic resonance) spectroscopy and high-resolution electron microscopy.

Identifying different states of the protein is only the first step in characterising the mechanism of amyloid formation: each species must be put in context within a sequence of molecular events, i.e. a pathway needs to be defined. To do this, we have set up a screen to identify optimum conditions for observing fibre formation in vitro.

Time courses will be recorded when the reaction is initiated from a number of different states of the protein including the dimeric form. This will not only establish a mechanism for the first time but it will also provide an experimental system which can be used to screen for potential therapeutic drugs.

Publications

Show: Featured publications All publications

Featured publications

Journal articles

Jelinska C, Davis PJ, Kenig M, Zerovnik E, Kokalj SJ, Gunčar G, Turk D, Turk V, Clarke DT, Waltho JP & Staniforth RA (2011) . Biophys J, 100(9), 2268-2274.
Žerovnik E, Staniforth RA & Turk D (2010) . Biochimie, 92(11), 1597-1607.
Milanesi L, Jelinska C, Hunter CA, Hounslow AM, Staniforth RA & Waltho JP (2008) . Biochemistry, 47(51), 13620-13634.
Morgan GJ, Giannini S, Hounslow AM, Craven CJ, Zerovnik E, Turk V, Waltho JP & Staniforth RA (2008) . J Mol Biol, 375(2), 487-498.
Sanders A, Jeremy Craven C, Higgins LD, Giannini S, Conroy MJ, Hounslow AM, Waltho JP & Staniforth RA (2004) . J Mol Biol, 336(1), 165-178.
Staniforth RA, Giannini S, Higgins LD, Conroy MJ, Hounslow AM, Jerala R, Craven CJ & Waltho JP (2001) . EMBO J, 20(17), 4774-4781.
Staniforth RA, Dean JL, Zhong Q, Zerovnik E, Clarke AR & Waltho JP (2000) . Proc Natl Acad Sci U S A, 97(11), 5790-5795.
Staniforth RA, Burston SG, Atkinson T & Clarke AR (1994) . Biochem J, 300 ( Pt 3), 651-658.
Staniforth RA, Burston SG, Smith CJ, Jackson GS, Badcoe IG, Atkinson T, Holbrook JJ & Clarke AR (1993) . Biochemistry, 32(15), 3842-3851.
Jackson GS, Staniforth RA, Halsall DJ, Atkinson T, Holbrook JJ, Clarke AR & Burston SG (1993) . Biochemistry, 32(10), 2554-2563.

All publications

Journal articles

Taylor AIP & Staniforth RA (2022) . Frontiers in Neuroscience, 16.
Matuszyk MM, Garwood CJ, Ferraiuolo L, Simpson JE, Staniforth RA & Wharton SB (2022) . Journal of Neurochemistry, 160(4), 434-453.
Taylor AIP, Gahan LD, Chakrabarti B & Staniforth R (2020) . Journal of Chemical Physics, 153(2).
Dennison AJC, Jones RAL, Staniforth RA & Parnell AJ (2016) . Soft Matter, 12(3), 824-829.
Davis PJ, Holmes D, Waltho JP & Staniforth RA (2015) . Journal of Molecular Biology, 427(15), 2418-2434.
Taler-Verčič A, Kirsipuu T, Friedemann M, Noormägi A, Polajnar M, Smirnova J, Znidarič MT, Zganec M, Skarabot M, Vilfan A , Staniforth RA et al (2013) . Int J Mol Sci, 14(9), 18362-18384.
Paramore R, Morgan GJ, Davis PJ, Sharma CA, Hounslow A, Taler-Verčič A, Žerovnik E, Waltho JP, Cliff MJ & Staniforth RA (2012) . Frontiers in Molecular Neuroscience(AUG 2012), 1-30.
Jelinska C, Davis PJ, Kenig M, Zerovnik E, Kokalj SJ, Gunčar G, Turk D, Turk V, Clarke DT, Waltho JP & Staniforth RA (2011) . Biophys J, 100(9), 2268-2274.
Žerovnik E, Stoka V, Mirtič A, Gunčar G, Grdadolnik J, Staniforth RA, Turk D & Turk V (2011) . FEBS J, 278(13), 2263-2282.
Zerovnik E, Staniforth RA & Turk D (2010) . Biochimie, 92(11), 1597-1607.
Žerovnik E, Staniforth RA & Turk D (2010) . Biochimie, 92(11), 1597-1607.
Milanesi L, Jelinska C, Hunter CA, Hounslow AM, Staniforth RA & Waltho JP (2008) . Biochemistry, 47(51), 13620-13634.
Morgan GJ, Giannini S, Hounslow AM, Craven CJ, Zerovnik E, Turk V, Waltho JP & Staniforth RA (2008) . J Mol Biol, 375(2), 487-498.
Zerovnik E, Skarabot M, Skerget K, Giannini S, Stoka V, Jenko-Kokalj S & Staniforth RA (2007) . Amyloid, 14(3), 237-247.
Jenko Kokalj S, Guncar G, Stern I, Morgan G, Rabzelj S, Kenig M, Staniforth RA, Waltho JP, Zerovnik E & Turk D (2007) . J Mol Biol, 366(5), 1569-1579.
Cliff MJ, Alizadeh T, Jelinska C, Craven CJ, Staniforth RA & Waltho JP (2006) . J Mol Biol, 364(4), 810-823.
Reed MAC, Jelinska C, Syson K, Cliff MJ, Splevins A, Alizadeh T, Hounslow AM, Staniforth RA, Clarke AR, Craven CJ & Waltho JP (2006) . J Mol Biol, 357(2), 365-372.
Kenig M, Jenko-Kokalj S, Tusek-Znidaric M, Pompe-Novak M, Guncar G, Turk D, Waltho JP, Staniforth RA, Avbelj F & Zerovnik E (2006) . Proteins, 62(4), 918-927.
Sanders A, Jeremy Craven C, Higgins LD, Giannini S, Conroy MJ, Hounslow AM, Waltho JP & Staniforth RA (2004) . J Mol Biol, 336(1), 165-178.
Staniforth RA, Giannini S, Higgins LD, Conroy MJ, Hounslow AM, Jerala R, Craven CJ & Waltho JP (2001) . EMBO J, 20(17), 4774-4781.
Staniforth RA, Dean JL, Zhong Q, Zerovnik E, Clarke AR & Waltho JP (2000) . Proc Natl Acad Sci U S A, 97(11), 5790-5795.
Staniforth RA, Giannini S, Bigotti MG, Cutruzzolà F, Travaglini-Allocatelli C & Brunori M (2000) . J Mol Biol, 297(5), 1231-1244.
Travaglini-Allocatelli C, Cutruzzolà F, Bigotti MG, Staniforth RA & Brunori M (1999) . J Mol Biol, 289(5), 1459-1467.
Travaglini-Allocatelli C, Cutruzzola F, Bigotti MG, Staniforth RA & Brunori M (1999) Folding mechanism of Pseudomonas aeruginosa cytochrome c(551): Role of electrostatic interactions on the hydrophobic collapse and transition state properties.. FASEB J, 13(7), A1387-A1387.
Bigotti MG, Allocatelli CT, Staniforth RA, Arese M, Cutruzzolà F & Brunori M (1998) . FEBS Lett, 425(3), 385-390.
Staniforth RA, Bigotti MG, Cutruzzolà F, Allocatelli CT & Brunori M (1998) . J Mol Biol, 275(1), 133-148.
Staniforth RA, Burston SG, Atkinson T & Clarke AR (1994) . Biochem J, 300 ( Pt 3), 651-658.
Staniforth RA, Cortés A, Burston SG, Atkinson T, Holbrook JJ & Clarke AR (1994) . FEBS Lett, 344(2-3), 129-135.
Staniforth RA, Burston SG, Smith CJ, Jackson GS, Badcoe IG, Atkinson T, Holbrook JJ & Clarke AR (1993) . Biochemistry, 32(15), 3842-3851.
Jackson GS, Staniforth RA, Halsall DJ, Atkinson T, Holbrook JJ, Clarke AR & Burston SG (1993) . Biochemistry, 32(10), 2554-2563.
Taylor AIP, Davis PJ, Aubrey LD, White JBR, Parton ZN & Staniforth RA () . ACS Chemical Neuroscience.

Conference proceedings papers

Gahan LD, Taylor AIP, Chakrabarti BJ, Hawkins RJ & Staniforth RA (2021) Coarse grained simulations of amyloidogenic proteins in the context of Alzheimer's disease. EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, Vol. 50(SUPPL 1) (pp 123-123)
Dennison AJ, Watkins EB, Parnell AJ, Staniforth RA & Jones RA (2013) Phosphatidylcholine Membranes in Denaturing Conditions and Binding of Partially Denatured Proteins. EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, Vol. 42 (pp S148-S148)
PARKER M, BURSTON S, JACKSON G, SPENCER J, STANIFORTH R & CLARKE A (1995) CHARACTERIZATION OF THE STRUCTURAL AND ENERGETIC PROPERTIES OF THE INTERMEDIATES ON THE FOLDING PATHWAY OF PGK FROM BACILLUS-STEAROTHERMOPHILUS. PROTEIN ENGINEERING, Vol. 8 (pp 22-22)

Preprints

Taylor AIP, Gahan LD, Staniforth RA & Chakrabarti B (2019) A Two-Step Biopolymer Nucleation Model Shows a Nonequilibrium Critical Point, arXiv.

Professional activities and memberships

2001: Royal Society University Research Fellowship
2000: Wellcome Trust Career Development Fellowship
1994: Wellcome Trust Travelling Research Fellowship to Europe

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School of Biosciences

School of Biosciences

Dr Rosie Staniforth

Featured publications

Journal articles

All publications

Journal articles

Conference proceedings papers

Preprints

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