Solution NMR Studies of Aβ Monomers and Oligomers

Early-Onset Parkinson Mutation Remodels Monomer–Fibril Interactions to Allosterically Amplify Synuclein’s Amyloid Cascade

“…In its monomeric form, αS is an intrinsically disordered protein (IDP) that samples a wide range of dynamic conformations, including both “closed” and “open” states (Figure B). − Closed conformers are stabilized by electrostatic interactions between the positively and negatively charged αS N- and C-termini (NTR and CTR), respectively, which occlude the aggregation-prone and fibrillization-essential non-amyloid-β component (NAC) region (Figure A, B). In the open conformers, the NAC segment is exposed and available to self-associate into oligomers and fibrils (Figure A, B). ,, Once formed, wild-type (wt) αS fibrils recruit additional monomers primarily through electrostatic interactions between the fibril C-terminus and the monomer N-terminus, driving closed-to-open monomer transitions and promoting secondary nucleation and further elongation of αS fibrils. − Understanding how PD-related mutations alter these self-association equilibria from monomer to fibrils (Figure B) is essential to understanding the molecular etiology of PD and possibly other amyloid-driven dementias. − …”