Dissecting the mechanisms of fibril-mediated amyloid toxicity (360G-Wellcome-093794_Z_10_Z)

£142,890

Amyloid-forming proteins chiefly recognised for their association with age-related neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are also responsible for a host of debilitating systemic and localised amyloidoses, including Diabetes Mellitus Type 2 and Dialysis Related Amyloidosis (DRA). Despite the frequency of these disorders within human populations, no effective cures are currently available for these conditions. Decades of research have established two main hypotheses for amyloid-associated cytotoxicity which implicates either soluble oligomers or mature amyloid fibrils as the primary determinants of cell death. However, recent data suggest the two may be linked. Several experiments have shown that mature fibrils are dynamic entities, releasing soluble material with cytotoxic potential. Others have highlighted that increasing the surface hydrophobicity of soluble toxic oligomers while maintaining a high degree of intermolecular beta-sheet structure greatly enhances their cytotoxic potential. Surface hydrophobicity is also increased among shorter B2m amyloid fibrils (Fig. 1a), which are known to be more cytotoxic than their longer counterparts. This raises the possibility that toxic oligomers and mature amyloid fibrils share common structural and/or chemical/physical properties that endow their cytotoxic potential. In this proposal, we will investigate whether fibril hydrophobicity and dynamics are key mediators of amyloid-associated toxicity. By using four different amyloid-forming sequences including AB1-40/42, B2-microglobulin (B2m) and ccB-p, we will determine: 1. Accurate fibril length distributions of AB1-40/42 and ccB-p amyloid fibrils 2. The role of hydrophobicity in fibril-associated cytotoxicity 3. How 'molecular recycling' properties of fibrils affect cytotoxicity 4. Structural elucidation of fibril-cell interactions This project will take a multidisciplinary approach, combining biophysical and cell biological experiments under the leadership of Prof. S.E. Radford and Dr E.W. Hewitt. Cryo-tomography techniques will be developed with Prof. H. Saibil (Birkbeck College, London) and mass spectrometry will be performed in collaboration with Prof. A.E. Ashcroft.

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Grant Details

Amount Awarded 142890
Applicant Surname Tipping
Approval Committee Molecules, Genes and Cells Funding Committee
Award Date 2010-06-14T00:00:00+00:00
Financial Year 2009/10
Grant Programme: Title PhD Studentship (Basic)
Internal ID 093794/Z/10/Z
Lead Applicant Mr Kevin Tipping
Partnership Value 142890
Planned Dates: End Date 2014-09-30T00:00:00+00:00
Planned Dates: Start Date 2010-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Yorkshire and the Humber
Sponsor(s) Prof Alan Berry