Functionally different α-synuclein inclusions yield insight into Parkinson’s disease pathology

C.C. Raiss, Theresa S. Braun, Irene B.M. Siemerink-Konings, Heinrich Grabmayr, Gerrit Cornelis Hassink, A. Sidhu, Jakob le Feber, Andreas R. Bausch, Casper Jansen, Vinod Subramaniam, Mireille Maria Anna Elisabeth Claessens

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Abstract

The formation of α-synuclein (α-S) amyloid aggregates, called Lewy bodies (LBs), is a hallmark of Parkinson’s disease (PD). The function of LBs in the disease process is however still unclear; they have been associated with both neuroprotection and toxicity. To obtain insight into this contradiction, we induced the formation of α-S inclusions, using three different induction methods in SH-SY5Y cells and rat-derived primary neuronal cells. Using confocal and STED microscopy we observed induction-dependent differences in α-S inclusion morphology, location and function. The aggregation of α-S in functionally different compartments correlates with the toxicity of the induction method measured in viability assays. The most cytotoxic treatment largely correlates with the formation of proteasome-associated, juxta-nuclear inclusions. With less toxic methods cytosolic deposits that are not associated with the proteasome are more prevalent. The distribution of α-S over at least two different types of inclusions is not limited to cell models, but is also observed in primary neuronal cells and in human mesencephalon. The existence of functionally different LBs, in vivo and in vitro, gives important insights in the impact of Lewy Body formation on neuronal functioning and may thereby provide a platform for discovering therapeutics.
Original languageEnglish
Article number23116
Number of pages13
JournalScientific reports
Volume6
DOIs
Publication statusPublished - 17 Mar 2016

Keywords

  • BSS-Neurotechnology and cellular engineering
  • molecular neurobiology
  • IR-100276
  • METIS-316906
  • EWI-26969

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