Williams AD, Sega M, Chen M, Kheterpal I, Geva M, Berthelier V, Kaleta DT, Cook KD, Wetzel R.
Structural properties of Abeta protofibrils stabilized by a small molecule.
Proc Natl Acad Sci U S A. 2005 May 17;102(20):7115-20.
PubMed.
Indeed, since some time I have been thinking about the need to search for protofibril stabilizers, i.e., substances, possibly but not necessarily amphipathic, able to interact with early oligomers of misfolded proteins or peptides by masking their exposed hydrophobic patches. Such an approach might make prefibrillar aggregates more stable, allowing them not only to arrest their growth into more stable and less toxic mature fibrils (which might appear undesirable), but also to make them much less toxic. This view is conceivable if we assume that toxicity is, at least in most cases, a consequence of aggregate instability and surface activity following exposure of hydrophobic clusters, allowing them to interact with other cellular components, notably membranes.
The revised paper apparently proceeds in this direction and it appears very important to check whether the CLC-induced protofibrils display the same toxicity to cells as those obtained in the absence of CLC. I expect they are much less toxic, but I am keen to read these data.
Comments
University of Florence
Indeed, since some time I have been thinking about the need to search for protofibril stabilizers, i.e., substances, possibly but not necessarily amphipathic, able to interact with early oligomers of misfolded proteins or peptides by masking their exposed hydrophobic patches. Such an approach might make prefibrillar aggregates more stable, allowing them not only to arrest their growth into more stable and less toxic mature fibrils (which might appear undesirable), but also to make them much less toxic. This view is conceivable if we assume that toxicity is, at least in most cases, a consequence of aggregate instability and surface activity following exposure of hydrophobic clusters, allowing them to interact with other cellular components, notably membranes.
The revised paper apparently proceeds in this direction and it appears very important to check whether the CLC-induced protofibrils display the same toxicity to cells as those obtained in the absence of CLC. I expect they are much less toxic, but I am keen to read these data.
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