Membrane activity of amyloid fibrils: unravelling .. (AMYLOID)
Membrane activity of amyloid fibrils: unravelling cell killing mechanism
Start date: Nov 1, 2011,
End date: Oct 31, 2013
"Numerous pathological conditions, designated as misfolding diseases, involve conversion of specific proteins from their native, soluble state to highly ordered filamentous polymers. For many years these amyloid fibrils were considered to be inert end-products of the aggregation pathway, while the toxic properties were mainly attributed to soluble oligomeric intermediates. A recent study demonstrated that fully assembled amyloid fibrils induce cell death, and the observed toxic effects are inversely correlated with fibril length (Xue at al. J. Biol. Chem. 2009, 284, 34272-34282). The findings pointed out that membrane damage may be involved in the cell injury, however the detailed mechanism by which fibrils kill cells remains to be resolved.The proposed research is one of the first studies aiming to shed light on this important question through systematic investigation of fibril-membrane interactions. Specifically, screening distinct lipid components will be performed in order to allocate membrane binding to specific cellular targets. The impact of fibrillar dimensions on the membrane activity of the aggregates and their interactions with specific lipid components will be evaluated. Additional factors, such as pH and protein charge, will be investigated. The study will include several amyloidogenic proteins in order to assess the generic nature of the killing mechanism."
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