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57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

12. - 15.09.2012, Erlangen

Banner: 57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie

Increased toxicity of extracellular alpha-synuclein following Bafilomycin A1 treatment occurs without enhancing aggregate release

Meeting Abstract

  • presenting/speaker Anne-Maria Pöhler - University Hospital Erlangen, Department of Molecular Neurology, Erlangen, Germany
  • Wei Xiang - Friedrich-Alexander University Erlangen-Nuremberg, Department of Biochemistry (Emil-Fischer-Zentrum), Erlangen, Germany
  • Ursula Schlötzer-Schrehardt - University Hospital Erlangen, Department of Ophthalmology, Erlangen, Germany
  • Holger Meixner - University Hospital Erlangen, Department of Molecular Neurology, Erlangen, Germany
  • Jürgen Winkler - University Hospital Erlangen, Department of Molecular Neurology, Erlangen, Germany
  • Jochen Klucken - University Hospital Erlangen, Department of Molecular Neurology, Erlangen, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnPP4.19

DOI: 10.3205/12dgnn096, URN: urn:nbn:de:0183-12dgnn0965

Veröffentlicht: 11. September 2012

© 2012 Pöhler et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Alpha-synuclein (aSyn) aggregation plays a crucial role in synucleinopathies such as Parkinson's disease and Dementia with Lewy bodies. Recently, we have shown that autophagy influences the aggregation process in a cell culture model of aSyn aggregation. This model consists of transient transfected H4 neuroglioma cells with a C-terminally modified aSyn (SynT) resulting in ThioS positive aSyn aggregates, in contrast to transfection with unmodified aSyn (non-aggregating aSyn). Here, inhibition of autophagy by Bafilomycin A1 (BafA1) reduced the number of aggregate bearing cells paralleled by a substantial increase of cellular toxicity. Interestingly, a more detailed analysis revealed that the toxic effect of BafA1 was mainly observed in close proximity to SynT positive cells. Furthermore, ultrastructural and biochemical analysis indicated that aSyn immunoreactive aggregates are partially released from H4 cells. Both findings suggest that secreted aSyn species may be linked to the increase in toxicity within the pericellular microenvironment. Indeed, SynT transfected cells show significantly more aSyn in the supernatant compared to non-aggregating aSyn transfected cells. Even though BafA1 treatment reduced the number of aggregate bearing cells this process was not paralleled by enhanced aggregate secretion. Furthermore, immunocytochemical analysis of SynT positive cells revealed obvious morphological changes of intracellular aSyn accumulations towards a more dense and punctate phenotype. Taken together, these findings suggest that the autophagy inhibitor BafA1 affects the aggregate formation process rather than the release of aggregates and oligomerized aSyn. Moreover the composition of released aSyn species (e.g. posttranslational modification or oligomerization) might define the toxicity for the surrounding microenvironment.