The molecular determinants of the aggregation and toxicity of peptides and proteins

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

Proteins are the building blocks of human cells and they direct the wide range of chemical reactions that are needed by a living creature. However proteins also cause a range of diseases, mostly those that affect the brains of older people, such as Alzheimer’s, Parkinson’s and motor neurone disease. In these disorders proteins stick together and become lodged in tissues, such as the brain, causing damage. We have looked at how proteins stick together in experiments that we carry out in test tubes and we have developed a computer program that can tell in advance how sticky a particular protein will be. Our recent work has shown that this program can also tell us how toxic a protein will be if it is introduced into the brain of a fruit fly. Although the fly brain is small there are many similarities with the human brain. We expect that by understanding exactly what makes a protein sticky and toxic in the fly brain we will be able to stop the same processes in the human brain. We might be able to do this by developing medicines that change the way proteins stick together to make them harmless.

Technical Summary

This proposal brings together a group of people with a wide range of skills from the Departments of Chemistry, Physics, Nanoscience, Genetics and Medicine to investigate the fundamental causes of a range of diseases that are caused by protein misfolding and aggregation. Our project is based on three key advances that have occurred in Cambridge, the first is the understanding that the potential to form amyloid fibrils is a common, if not fundamental, property of all proteins. The second is the discovery that we can accurately predict the aggregation propensity of proteins knowing only their amino acid sequences. The third advance has been the development of Drosophila models of protein aggregation diseases. We will focus on understanding the fundamental mechanisms that underlie a range of protein misfolding disorders and use our range of skills to carefully observe protein aggregation in the test tube, interpret the data using sophisticated computer algorithms and use Drosophila model systems to provide further insights into pathological significance. We will extend our preliminary studies on the Abeta peptide and investigate other proteins implicated in neurological disorders and so formulate a quantitative model that describes the molecular determinants of peptide and protein aggregation and toxicity. Such a powerful understanding of fundamental disease mechanisms will provide us with new opportunities and strategies for therapeutic intervention.

Publications

10 25 50
 
Description ART Major Research Grant
Amount £154,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 10/2011
 
Description Alzheimer's Research UK Senior Fellowship (for D.C. Crowther)
Amount £190,000 (GBP)
Funding ID ART-SRF2010-2 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 10/2013
 
Description BB/H003843/1 Quantitative approaches to defining normal and aberrant protein homeostasis
Amount £1,975,342 (GBP)
Funding ID BB/H003843/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 10/2015
 
Description Wellcome/MRC Neurodegeneration initiative
Amount £5,000,000 (GBP)
Funding ID MC_G1000734 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 10/2015
 
Title Computer vision locomotor assay 
Description iFly is computer vision equipment and software that allows the detailed analysis of fly locomotion. This allows the very early detection of subtle deficits that accompany neurodegeneration 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact This will greatly accelerate screening of genes and compounds for efficacy against the disease related phenotypes in the flies. 
 
Title Drosophila model of Abeta toxicity in Alzheimer's disease 
Description We express the human Abeta peptide in the brain of Drosophila melanogaster and see phenotypes including reduced lifespan, locomotor dysfunction and neurodegeneration. 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2006 
Provided To Others? Yes  
Impact Rapid in vivo model for investigating the biological relevance of in vitro theories of protein aggregation. Also good for performing genetic screens and finding pathways of disease. 
 
Title Various other models of human neurodegenerative diseases 
Description We express the human proteins and peptides in the brain of Drosophila melanogaster and see phenotypes including reduced lifespan, locomotor dysfunction and neurodegeneration. 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2006 
Provided To Others? Yes  
Impact Allow investigation of a range of neurodegenerative diseases caused by protein aggregation 
 
Description Cambridge University Neurodegeneration Consortium 
Organisation University of Bristol
Department Centre for Comparative & Clinical Anatomy (CCCA)
Country United Kingdom 
Sector Academic/University 
PI Contribution This substantial grant was awarded to Prof. Peter St.George-Hyslop by MRC/Wellcome Trust. My groups role is to interface between the theoretical chemists who are expert in the molecular mechanisms of protein folding and misfolding and neuroscience. In particular we use Drosophila model systems to bridge the disciplinary gap.
Collaborator Contribution The consortium has a series of collaborative meetings where we share data and discuss ongoing collaboration.
Impact Industrial sponsorship has been attracted.
Start Year 2008
 
Description Human, worm and fly screening 
Organisation Medical Research Council (MRC)
Department MRC Functional Genomics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution I wrote the grant and mentored the postdoc who is working on the project. My group will host the fly work.
Collaborator Contribution Introduced the group to worm models of protein misfolding diseases
Impact We have a review in TIBS in press and we are co-organising a mini-symposium at ICAD2010, an international Alzheimer's disease meeting.
Start Year 2007
 
Description Role of extracellular chaperones in Alzheimer's disease 
Organisation University of Wollongong
Country Australia 
Sector Academic/University 
PI Contribution I have co-ordinated the work of two postdoctoral fellows and liased with the University of Wollongong. The work has consisted of in vitro, biophysical work, and in vivo experiments using our Drosophila model systems.
Collaborator Contribution We have hosted a postdoctoral fellow who worked on in vitro and in vivo models of protein misfolding diseases. This has resulted in a paper that is currently under review.
Impact paper under review looking at the generic mechanism of protein aggregate toxicity.
Start Year 2008
 
Description Stabilising alpha helical structure to prevent amyloid formation 
Organisation Uppsala University
Country Sweden 
Sector Academic/University 
PI Contribution I supervise the PhD student and am working to write a postdoctoral fellowship.
Collaborator Contribution A graduate student is working in my lab looking at the ability of an extracellular chaperone to modulate Abeta toxicity in our fly model system.
Impact 16849336 19458258
Start Year 2006
 
Company Name Floceleris 
Description Company that is seeking commercial partners for a seeded aggregation assay that may be used for the detection of seeded aggregation in clinical samples. This may provide a test to detect the pathological processes underpinning a number of neurodegenerative disorders. 
Year Established 2012 
Impact Winner of the Cambridge University Entrepreneurs, Carpe Diem Life Science Start-up of the Year 2013. Incorporated as a limited company in October 2013.
Website http://www.floceleris.com/
 
Description Alzheimer Research UK public meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 50 members of the public attended the annual meeting to hear about dementia research in clinical and basic domains.

nil
Year(s) Of Engagement Activity 2013
URL http://www.alzheimer.group.cam.ac.uk/
 
Description Cambridge Science week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We had an exhibition of our work using flies as models of neurodegeneration in the department of Chemistry in Cambridge.

Publicity and communication.
Year(s) Of Engagement Activity 2008
 
Description Local TV news interview about research 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I was interviewed for about 2 min in an article about Alzheimer's disease on the local TV news (Look East).

I got positive feedback from the public and from the Alzheimer's research trust who organised the interview.
Year(s) Of Engagement Activity 2009
 
Description Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Was interviewed on Radio Cambridgeshire about the work on Alzheimer's disease.

Publicity.
Year(s) Of Engagement Activity 2007
 
Description School visit - Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk biannually to a local 6th form college to the medical society.

We get summer students working in the lab.
Year(s) Of Engagement Activity 2007,2009,2011,2013
 
Description Websites 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Various websites contributed to: www.gpnotebook.co.uk http://www.neuroscience.cam.ac.uk/directory/profile.php?damiancrowther http://web.me.com/damiancrowther/Site/Welcome.html

Publicity and explanation of our work for the public: http://web.me.com/damiancrowther/Site/FAQ.html
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014