TY - JOUR

T1 - The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation

AU - Lorenzen, Nikolai

AU - Nielsen, Søren Bang

AU - Buell, Alexander K.

AU - Kaspersen, Jørn Døvling

AU - Arosio, Paolo

AU - Vad, Brian Stougaard

AU - Paslawski, Wojciech

AU - Christiansen, Gunna

AU - Valnickova Hansen, Zuzana

AU - Andreasen, Maria

AU - Enghild, Jan Johannes

AU - Pedersen, Jan Skov

AU - Dobson, Christopher M

AU - Knowles, Tuomas P J

AU - Otzen, Daniel

PY - 2014/2/16

Y1 - 2014/2/16

N2 - Studies of protein amyloid formation have revealed that potentially cytotoxic oligomers frequently accumulate during fibril formation. An important question in the context of mechanistic studies of this process is whether or not oligomers are intermediates in the process of amyloid fibril formation, either as precursors of fibrils or as species involved in the fibril elongation process or instead if they are associated with an aggregation process that is distinct from that generating mature fibrils. Here we describe and characterize in detail two well-defined oligomeric species formed by the protein α-synuclein (αSN), whose aggregation is strongly implicated in the development of Parkinson’s disease (PD). The two types of oligomers are both formed under conditions where amyloid fibril formation is observed but differ in molecular weight by an order of magnitude. Both possess a degree of β-sheet structure that is intermediate between that of the disordered monomer and the fully structured amyloid fibrils, and both have the capacity to permeabilize vesicles in vitro. The smaller oligomers, estimated to contain ~30 monomers, are more numerous under the conditions used here than the larger ones and small-angle x-ray scattering (SAXS) data suggest that they are ellipsoidal with a high degree of flexibility at the interface with solvent. This oligomer population is unable to elongate fibrils, and indeed results in an inhibition of the kinetics of amyloid formation in a concentration-dependent manner.

AB - Studies of protein amyloid formation have revealed that potentially cytotoxic oligomers frequently accumulate during fibril formation. An important question in the context of mechanistic studies of this process is whether or not oligomers are intermediates in the process of amyloid fibril formation, either as precursors of fibrils or as species involved in the fibril elongation process or instead if they are associated with an aggregation process that is distinct from that generating mature fibrils. Here we describe and characterize in detail two well-defined oligomeric species formed by the protein α-synuclein (αSN), whose aggregation is strongly implicated in the development of Parkinson’s disease (PD). The two types of oligomers are both formed under conditions where amyloid fibril formation is observed but differ in molecular weight by an order of magnitude. Both possess a degree of β-sheet structure that is intermediate between that of the disordered monomer and the fully structured amyloid fibrils, and both have the capacity to permeabilize vesicles in vitro. The smaller oligomers, estimated to contain ~30 monomers, are more numerous under the conditions used here than the larger ones and small-angle x-ray scattering (SAXS) data suggest that they are ellipsoidal with a high degree of flexibility at the interface with solvent. This oligomer population is unable to elongate fibrils, and indeed results in an inhibition of the kinetics of amyloid formation in a concentration-dependent manner.

KW - synuclein

KW - aggregation

KW - amyloid fibril

KW - elongation

KW - growth

U2 - 10.1021/ja411577t

DO - 10.1021/ja411577t

M3 - Journal article

C2 - 24527756

VL - 136

SP - 3859

EP - 3868

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 10

ER -