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In vivo protein complementation demonstrates presynaptic α-synuclein oligomerization and age-dependent accumulation of 8-16-mer oligomer species

Intracellular accumulation of α-synuclein (α-syn) and formation of Lewy bodies are neuropathological characteristics of Parkinson’s disease (PD) and related α-synucleinopathies. Oligomerization and spreading of α-syn from neuron to neuron have been suggested as key events contributing to the progres...

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Main Authors: Kiechle, Martin (Author) , von Einem, Bjoern (Author) , Höfs, Lennart (Author) , Voehringer, Patrizia (Author) , Grozdanov, Veselin (Author) , Markx, Daniel (Author) , Parlato, Rosanna (Author) , Wiesner, Diana (Author) , Mayer, Benjamin (Author) , Sakk, Olena (Author) , Baumann, Bernd (Author) , Lukassen, Soeren (Author) , Liß, Birgit (Author) , Ekici, Arif Bülent (Author) , Ludolph, Albert C. (Author) , Walther, Paul (Author) , Ferger, Boris (Author) , McLean, Pamela J. (Author) , Falkenburger, Björn (Author) , Weishaupt, Jochen H. (Author) , Danzer, Karin M. (Author)
Format: Article (Journal)
Language:English
Published: 26 November 2019
In: Cell reports
Year: 2019, Volume: 29, Issue: 9, Pages: 2862-2874.e9
ISSN:2211-1247
DOI:10.1016/j.celrep.2019.10.089
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Author Notes:authors: Martin Kiechle, Bjoern von Einem, Lennart Höfs, Patrizia Voehringer, Veselin Grozdanov, Daniel Markx, Rosanna Parlato, Diana Wiesner, Benjamin Mayer, Olena Sakk, Bernd Baumann, Soeren Lukassen, Birgit Liss, Arif B. Ekici, Albert C. Ludolph, Paul Walther, Boris Ferger, Pamela J. McLean, Björn H. Falkenburger, Jochen H. Weishaupt, Karin M. Danzer
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Summary:Intracellular accumulation of α-synuclein (α-syn) and formation of Lewy bodies are neuropathological characteristics of Parkinson’s disease (PD) and related α-synucleinopathies. Oligomerization and spreading of α-syn from neuron to neuron have been suggested as key events contributing to the progression of PD. To directly visualize and characterize α-syn oligomerization and spreading in vivo, we generated two independent conditional transgenic mouse models based on α-syn protein complementation assays using neuron-specifically expressed split Gaussia luciferase or split Venus yellow fluorescent protein (YFP). These transgenic mice allow direct assessment of the quantity and subcellular distribution of α-syn oligomers in vivo. Using these mouse models, we demonstrate an age-dependent accumulation of a specific subtype of α-syn oligomers. We provide in vivo evidence that, although α-syn is found throughout neurons, α-syn oligomerization takes place at the presynapse. Furthermore, our mouse models provide strong evidence for a transsynaptic cell-to-cell transfer of de novo generated α-syn oligomers in vivo.
Item Description:Gesehen am 08.07.2021
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2019.10.089

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