Solution conditions determine the relative importance of nucleation and growth processes in alpha-synuclein aggregation

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


The formation of amyloid fibrils by the intrinsically disordered protein alpha-synuclein is a hallmark of Parkinson disease. To characterize the microscopic steps in the mechanism of aggregation of this protein we have used in vitro aggregation assays in the presence of preformed seed fibrils to determine the molecular rate constant of fibril elongation under a range of different conditions. We show that alpha-synuclein amyloid fibrils grow by monomer and not oligomer addition and are subject to higher-order assembly processes that decrease their capacity to grow. We also find that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which can lead to proliferation of the total number of aggregates, are undetectable. At pH values below 6, however, the rate of secondary nucleation increases dramatically, leading to a completely different balance between the nucleation and growth of aggregates. Thus, at mildly acidic pH values, such as those, for example, that are present in some intracellular locations, including endosomes and lysosomes, multiplication of aggregates is much faster than at normal physiological pH values, largely as a consequence of much more rapid secondary nucleation. These findings provide new insights into possible mechanisms of alpha-synuclein aggregation and aggregate spreading in the context of Parkinson disease.


  • Alexander K. Buell
  • Celine Galvagnion
  • Ricardo Gaspar
  • Emma Sparr
  • Michele Vendruscolo
  • Tuomas P. J. Knowles
  • Sara Linse
  • Christopher M. Dobson
Enheter & grupper

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biologiska vetenskaper
  • Fysikalisk kemi


Sidor (från-till)7671-7676
TidskriftProceedings of the National Academy of Sciences
StatusPublished - 2014
Peer review utfördJa