Organotypic slice culture model demonstrates inter-neuronal spreading of alpha-synuclein aggregates

Sara Elfarrash, Nanna Møller Jensen, Nelson Ferreira, Cristine Betzer, Jervis Vermal Thevathasan, Robin Diekmann, Mohamed Adel, Nisreen Mansour Omar, Mohamed Z Boraie, Sabry Gad, Jonas Ries, Deniz Kirik, Sadegh Nabavi, Poul Henning Jensen

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Here we describe the use of an organotypic hippocampal slice model for studying α-synuclein aggregation and inter-neuronal spreading initiated by microinjection of pre-formed α-synuclein fibrils (PFFs). PFF injection at dentate gyrus (DG) templates the formation of endogenous α-synuclein aggregates in axons and cell bodies of this region that spread to CA3 and CA1 regions. Aggregates are insoluble and phosphorylated at serine-129, recapitulating Lewy pathology features found in Parkinson's disease and other synucleinopathies. The model was found to favor anterograde spreading of the aggregates. Furthermore, it allowed development of slices expressing only serine-129 phosphorylation-deficient human α-synuclein (S129G) using an adeno-associated viral (AAV) vector in α-synuclein knockout slices. The processes of aggregation and spreading of α-synuclein were thereby shown to be independent of phosphorylation at serine-129. We provide methods and highlight crucial steps for PFF microinjection and characterization of aggregate formation and spreading. Slices derived from genetically engineered mice or manipulated using viral vectors allow testing of hypotheses on mechanisms involved in the formation of α-synuclein aggregates and their prion-like spreading.

Original languageEnglish
Article number213
JournalActa Neuropathologica Communications
Number of pages16
Publication statusPublished - 19 Dec 2019


  • Alpha-synuclein
  • Organotypic slices
  • Prion-like spreading
  • Serine-129 phosphorylation


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