Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose

Anna Carin Hoffmann, Georgia Minakaki, Stefanie Menges, Rachele Salvi, Sergey Savitskiy, Aida Kazman, Hugo Vicente Miranda, Dirk Mielenz, Jochen Klucken, Jürgen Winkler, Wei Xiang

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Abstract

Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.

Original languageEnglish
Article number544
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 24 Jan 2019

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alpha-Synuclein
Trehalose
Lysosomes
Endosomes
Autophagy
Proteasome Endopeptidase Complex
Organelles

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Hoffmann, A. C., Minakaki, G., Menges, S., Salvi, R., Savitskiy, S., Kazman, A., ... Xiang, W. (2019). Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose. Scientific Reports, 9(1), [544]. https://doi.org/10.1038/s41598-018-35811-8
Hoffmann, Anna Carin ; Minakaki, Georgia ; Menges, Stefanie ; Salvi, Rachele ; Savitskiy, Sergey ; Kazman, Aida ; Vicente Miranda, Hugo ; Mielenz, Dirk ; Klucken, Jochen ; Winkler, Jürgen ; Xiang, Wei. / Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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abstract = "Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.",
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Hoffmann, AC, Minakaki, G, Menges, S, Salvi, R, Savitskiy, S, Kazman, A, Vicente Miranda, H, Mielenz, D, Klucken, J, Winkler, J & Xiang, W 2019, 'Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose' Scientific Reports, vol. 9, no. 1, 544. https://doi.org/10.1038/s41598-018-35811-8

Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose. / Hoffmann, Anna Carin; Minakaki, Georgia; Menges, Stefanie; Salvi, Rachele; Savitskiy, Sergey; Kazman, Aida; Vicente Miranda, Hugo; Mielenz, Dirk; Klucken, Jochen; Winkler, Jürgen; Xiang, Wei.

In: Scientific Reports, Vol. 9, No. 1, 544, 24.01.2019.

Research output: Contribution to journalArticle

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AU - Hoffmann, Anna Carin

AU - Minakaki, Georgia

AU - Menges, Stefanie

AU - Salvi, Rachele

AU - Savitskiy, Sergey

AU - Kazman, Aida

AU - Vicente Miranda, Hugo

AU - Mielenz, Dirk

AU - Klucken, Jochen

AU - Winkler, Jürgen

AU - Xiang, Wei

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