Molecular mechanism of secondary nucleation on amyloid fibrils · revision history

Revision 2

Accepted · core change · record

Changes against revision 1:

Title
Molecular mechanism of secondary nucleation on amyloid fibrils
Plain
Some proteins stack into long fibers called amyloids, and the surface of an existing fiber speeds up the birth of new ones, which drives the self-amplifying aggregation seen in neurodegenerative disease. How the fiber surface does this, molecule by molecule, is unknown.
Precise · changed · core
Revision 1: For A-beta42 at neutral pH and $\alpha$-synuclein at mildly acidic pH (about 5 to 6) in vitro, aggregation kinetics fit a master equation in which secondary nucleation on fibril surfaces, at rate $k_{2}$ m^$n_{2}$ M (m = monomer concentration, M = fibril mass concentration), dominates the formation of new aggregates. Determine the microscopic steps (adsorption, conformational conversion on the surface, detachment) and compute k_2 and the reaction order n_2 from a molecular model, matching measured values within a factor of 3.
Revision 2: For A-beta42 at neutral pH and $\alpha$-synuclein at mildly acidic pH (about 5 to 6) in vitro, aggregation kinetics fit a master equation in which secondary nucleation on fibril surfaces, at rate $k_{2}$ m^$n_{2}$ M (m = monomer concentration, M = fibril mass concentration), dominates the formation of new aggregates. Determine the microscopic steps (adsorption, conformational conversion on the surface, detachment) and compute $k_{2}$ and the reaction order $n_{2}$ from a molecular model, matching measured values within a factor of 3.
Settled by
A molecular simulation or structural-kinetic model that predicts $k_{2}$ and $n_{2}$ and their dependence on sequence mutations, confirmed by bulk kinetics and single-fibril imaging.
Kind
well-posed
Answer type
mechanism
References
(empty)
Literature status
open
Status note
Kinetic analysis established secondary nucleation as the dominant source of new A-beta42 aggregates in 2013; its molecular steps remain unresolved.
Posed since
2013

Decisions