Compatibility rules for glycosaminoglycan-amyloid interactions

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Over 30 polypeptides self-assemble into insoluble amyloid fibrils associated with amyloid disease. As early as the 1850's it was found that amyloid deposits are associated with carbohydrates, later identified and classified as proteoglycans and glycosaminoglycan (GAG) polysaccharides. GAGs are now known to co-localise widely with amyloid assembled from a variety of protein precursors, and to influence fibril growth rate, fibril morphology, fibril stability and the pathogenic properties of the soluble pre-fibrillar intermediates. How the chemical composition of GAGs or their amyloid protein partners influence their molecular compatibility, however, remains unknown.

Capitalising on our exciting recent developments which have revealed the first atomic resolution structures of a fibril-GAG interaction, we propose here to determine the molecular determinants of fibril-GAG interactions using both natural and model GAGs and fibrils of Abeta1-40 and Abeta1-42 (associated with Alzheimer's disease), and amylin, the pancreatic islet amyloid polypeptide associated with type II diabetes. Using a combination of solid-state NMR and biochemical and biophysical techniques, we will determine how GAG-amyloid interactions are modulated by protein sequence, fibril architecture, and saccharide substitution patterns. We will establish the relative importance of different GAG family members as potential partners for interacting with amyloid fibrils and elucidate the structural consequences of binding at the detailed level of protein structure. Furthermore, the first details on how GAGs direct the early stages of amyloid assembly will be provided from structural measurements on assembly intermediates in the presence/absence of GAGs. A comprehensive atomistic dissection of these long-overlooked interactions will thus emerge, providing holistic insights into the amyloid assembly process and guidance for the design of therapeutic or diagnostic agents against amyloid assembly and disease.

Scientific impact: Protein self-aggregation has immense fundamental, biotechnological and medical importance. This project will have wide scientific impact by addressing key questions in the amyloid field: how and why do GAGs bind widely to amyloid fibrils irrespective of sequence and structure; how does GAG binding influence the course of amyloid assembly and how can we harness this information for the development of amyloid diagnostics and therapeutics? This is a challenge of vital biological importance; the results will be of interest to a wide spectrum of scientists, pharmacists and medical researchers in academia and industry.

Industrial impact: Details of amyloid-GAG interactions offer immense benefits for the design of therapeutic strategies targeting several, if not all, amyloid disorders. Amyloid disease is predicted to be the major threat to human health in Western society in the next 50 years. However, the lack of understanding of the origins of molecular recognition between amyloid and GAGs has hindered the development of rationally designed anti-amyloid therapies and diagnostics. The long-term collaboration between the applicants will answer this key question, building on excellent equipment, exemplary infrastructure and a strong record of success in this area. We will also use our close contacts with pharmaceutical companies (e.g, GSK, UCB (Parkinson's), Lilley (Tauopathies), AstraZeneca (AD, Diabetes)) to expedite the design of new anti-amyloid agents based on the results obtained: DAM has already designed novel anti-amyloids by utilizing structural data.

Supporting knowledge and technology translation: DAM, EAY and SER speak regularly at scientific conferences and are well versed in knowledge exchange with academics and industrialists. We anticipate that the high impact of this work will merit spotlight articles in widely read magazines and journals. DAM's work developing amyloid inhibitors has been highlighted in ACS Chemical Biology, SciBX and F1000. SER's research into amyloid fibril toxicity has been highlighted on the front page of the BBSRC website (6.12.2009), and chosen as paper of the week in J. Biol. Chem., illustrating the importance of the research in this area and the pro-active nature of the researchers in promoting its research findings.
There are excellent opportunities to develop the results into therapeutic or diagnostic agents. Systems are in place for patenting and exploiting new materials through the technology transfer arm of the University of Liverpool, Business Gateway, and its business incubator, MerseyBio that provides accommodation for start-up biotechnology companies. ER has active collaborations with UCB, Medimmune and Lilley, which will ensure facile links into these organisations once the project bears fruit. SER is the ACSMB Director, with overall responsibility for linking with Industry though the University of Leeds Industry Hub in pharmaceuticals.

Delivering highly skilled people: The applicants will train two PDRAs in cutting edge technology and ensure their successful career development in academia or industry. Over the past few years, highly skilled post-graduate and post-doctoral fellows from the laboratories of DAM, EAY and SER have gone on to fellowships, lectureships and positions in industry.

Public engagement: This work will have a large impact on the general public, many of whom are affected directly or indirectly by amyloid disease. The Institute of Integrative Biology at Liverpool has an active Public Engagement agenda of substantial breadth, and DAM and EAY will join existing outreach and inreach programs to publicise this work, for example by visiting local colleges and at Institute Open Days. At Leeds, ACSMB members regularly organise workshops and science fairs to inspire school children to study science, student placements in research laboratories, talks at conferences for school teachers and authorship of articles for sixth-formers.