Faculty of Biological Sciences

Research Bulletin

Researchers find clue to stopping Alzheimer's-like diseases

2nd July 2014

Tiny differences in mice that make them peculiarly resistant to a family of conditions that includes Alzheimer's, Parkinson's and Creutzfeldt-Jakob Disease may provide clues for treatments in humans.

Researchers find clue to stopping Alzheimer's-like diseasestitle=

Amyloid diseases are often incurable because drug designers cannot identify the events that cause them to start.

Professor Sheena Radford, Astbury Professor of Biophysics at the University of Leeds, said: "Amyloid diseases are associated with the build-up of fibrous plaques out of long strings of 'misfolding' proteins, but it is not clear what kicks the process off. That means the normal approach of designing a drug to destroy or disable the species that start the disease process does not work.

"We have to take a completely different tack: instead of targeting the cause of the disease, we need to disrupt the plaque building process."

The University of Leeds-led team's study, published in the journal Molecular Cell today, looked to mice for a way forward.

"We already knew that mice were not prone to the build up of some of these plaques. This study, for the first time, observed the building happening and saw the differences between the mice proteins and their almost identical human equivalents," Professor Radford said.

She added: "We mixed the mice and human proteins and found that the mice protein actually stopped the formation of the plaque-forming fibrils by the human protein."

The research was conducted completely in the test-tube using human and mice beta-2 microglobulin proteins produced in the laboratory. Plaques made up of beta-2 microglobulin are associated with Dialysis Related Amyloidosis (DRA). Instead of being a neurodegenerative condition like Alzheimer's or Parkinson's, DRA primarily affects the joints of people on kidney dialysis.

The team observed differences in the formation of the plaque-forming fibrils in samples containing only mice protein, samples with only the human protein and samples containing mixtures of the two.

The lead researcher, Dr Theodoros Karamanos, said: "These two versions of the proteins are almost exactly the same, with very slight differences in structure, but the outcomes are completely different. If I put a misfolding-prone protein in the human sample, I see the formation of fibrils in two days in the right conditions. If I do the same in the mouse sample, I can leave it for weeks and there are no fibrils.

Dr Karamanos added: "The exciting thing is that if you mix the proteins-with only one mouse protein for every five human proteins-you see a significant disruption of the formation of fibrils."

The study used Nuclear Magnetic Resonance spectroscopy to look at a molecular level at the interactions of the different proteins and identified tiny differences in the physical and chemical properties of the surfaces that made a great difference to whether plaques are formed.

The results showed that the mouse protein binds to the human protein more tightly than the human protein binds to its misfolded form. Interestingly, subtle differences in the driving forces of binding (i.e. the balance of hydrophobic and charge-charge interactions) in the binding interface govern the outcome of assembly.

Dr Karamanos said: "We can't just load up a syringe and inject mouse protein into patients. But if we know the properties of the interface between the two proteins that are responsible for the inhibition effect, we can ask the chemists to design small molecule drugs which mimic what the mouse protein does to the human protein. That may be a key insight into how to stop the plaque building process."

The project received funding from the Wellcome Trust and the European Research Council's Seventh Framework Programme.

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Recent Grants

Mike McPherson (and colleagues in the School of Chemistry), EPSRC (Jul 2014), £819,880

Sheena Radford, Univesity of Michigan (Jul 2014), £138,452

Chris West, Leverhulme Trust (Jun 2014), £181,241

Jon Lippiat, Darren Tomlinson, BBSRC (May 2014), £125,174

David Brockwell, Sheena Radford, Medimmune Ltd (Apr 2014), £337,661

Peter Stockley, Wellcome Trust (Apr 2014), £251,019

Mike McPherson, Wellcome Trust (Apr 2014), £146,596

Andrew Macdonald, Kidney Research Fund UK (Apr 2014), £127,237

Mike McPherson (and colleagues in School of Design), Technology Strategy Board (Apr 2014), £114,350

Paul Millner, Peter Stockley, Darren Tomlinson, YCR (Apr 2014), £95,874

Carrie Ferguson, Karen Birch, Shaunna Burke, Heart Research UK (Apr 2014), £60,140

Dave Westhead, MRC (Apr 2014), £18,304

Brendan Davies, BBSRC (Mar 2014), £451,829

Jim Deuchars, MRC (Mar 2014), £300,000

Adam Kupinski, Children with Cancer (Mar 2014), £50,000

Alison Baker, Steve Baldwin, BBSRC (Feb 2014), £403,439

Sarah Zylinski, BBSRC (Feb 2014), £355,869

Dave Lewis, Nigel Hooper, Tony Turner, Hugh Pearson, James Duce, Alzheimer's Society (Feb 2014), £29,871

Ronaldo Ichyama, Samit Chakrabarty, International Spinal Research Trust (Jan 2014), £304,600

Brendan Davies, BBSRC/Bayer Crop Science SA-NV (Jan 2014), £470,053

Adrian Goldman, Steve Baldwin, Stephen Muench, Thomas Edwards, Arwen Pearson , BBSRC (Jan 2014), £467,103

Stefan Kepinski, BBSRC (Jan 2014), £359,269

Elwyn Isaac, EU (Jan 2014), £179,445

Dave Westhead, Leukaemia & Lymphoma Research (Jan 2014), £105,937

John Barr, Thomas Edwards, MRC (Dec 2013), £469,505

Alex O'Neill, MRC (Dec 2013), £349,017

Darren Tomlinson, Yorkshire Cancer Research (Nov 2013), £142,334

Nikita Gamper, MRC (Nov 2013), £336,563

Keith Hamer, Alison Dunn, NERC (Nov 2013), £47,233

Alan Berry, Wellcome Trust (Oct 2013), £749,365

Urwin, Howard Atkinson, BBSRC (Oct 2013), £360,508

Eileen Ingham, Stacey-Paul Wilshaw, NHS R&D (Oct 2013), £356,623

Sheena Radford, BBSRC (Oct 2013), £329,906

Nigel Hooper, Alzheimer's Research (Oct 2013), £327,075

Eileen Ingham, EPSRC (Oct 2013), £276,751

David Beech, BHF (Oct 2013), £109,974

Mark Harris, Medical Research Foundation (Oct 2013), £34,455

James Dachtler, Royal Society (Oct 2013), £15,000

Ade Whitehouse, Teresa Rosenbaum Golden Charitable Trust (Oct 2013), £10,000

Jurgen Denecke, BBSRC (Sep 2013), £382,093

Andy Cuming, EU (Sep 2013), £257,714

Paul Knox, BBSRC (Sep 2013), £411,948

Vas Ponnambalam, Leverhulme Trust (Sep 2013), £245,031

Peter Meyer, EU (Sep 2013), £242,166

Dave Rowlands, Nic Stonehouse, EU (Sep 2013), £202,556

Derek Steele, BHF (Sep 2013), £103,629

Joan Boyes, NC3Rs (Sep 2013), £90,000

Peter Stockley, Royal Society (Sep 2013), £11,400

Darren Tomlinson, Leverhulme Trust (Sep 2013), £5,645

Nic Stonehouse, Dave Rowlands, BBSRC (Aug 2013), £574,906

Eileen Ingham, Wellcome Trust (Aug 2013), £191,470

Adrian Goldman, Royal Society (Aug 2013), £75,000

Mike McPherson, Wellcome Trust (Aug 2013), £40,000

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