Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology

J Neurochem. 2009 Oct;111(1):192-203. doi: 10.1111/j.1471-4159.2009.06324.x. Epub 2009 Aug 4.


Lewy bodies, alpha-synuclein (alpha-syn) immunopositive intracellular deposits, are the pathological hallmark of Parkinson's disease (PD). Interestingly, Lewybody-like structures have been identified in fetal tissue grafts about one decade after transplantation into the striatum of PD patients. One possible explanation for the accelerated deposition of alpha-syn in the graft is that the aggregation of alpha-syn from the host tissue to the graft is spread by a prion disease-like mechanism. We discuss here an in vitro model which might recapitulate some aspects of disease propagation in PD. We found here that in vitro-generated alpha-syn oligomers induce transmembrane seeding of alpha-syn aggregation in a dose- and time-dependent manner. This effect was observed in primary neuronal cultures as well as in neuronal cell lines. The seeding oligomers were characterized by a distinctive lithium dodecyl sulfate-stable oligomer pattern and could be generated in a dynamic process out of pore-forming oligomers. We propose that alpha-syn oligomers form as a dynamic mixture of oligomer types with different properties and that alpha-syn oligomers can be converted into different types depending on the brain milieu conditions. Our data indicate that extracellular alpha-syn oligomers can induce intracellular alpha-syn aggregation, therefore we hypothesize that a similar mechanism might lead to alpha-syn pathology propagation.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian
  • Humans
  • Intermediate Filament Proteins / chemistry*
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism*
  • Intermediate Filament Proteins / pharmacology*
  • Mice
  • Mutation / genetics
  • Neuroblastoma / pathology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / classification
  • Statistics, Nonparametric
  • Time Factors
  • Transfection / methods


  • Intermediate Filament Proteins
  • Peptide Fragments
  • desmuslin
  • Calcium