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

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Details zur Publikation

Autor(en): Hoffmann AC, Minakaki G, Menges S, Salvi R, Savitskiy S, Kazman A, Miranda HV, Mielenz D, Klucken J, Winkler J, Xiang W
Zeitschrift: Scientific Reports
Jahr der Veröffentlichung: 2019
Band: 9
Heftnummer: 1
ISSN: 2045-2322


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.


FAU-Autoren / FAU-Herausgeber

Hoffmann, Anna-Carin
Institut für Biochemie
Klucken, Jochen Prof. Dr.
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Menges, Stefanie
Professur für Molekulare Neurologie
Mielenz, Dirk Prof. Dr.
Medizinische Fakultät
Minakaki, Georgia
Professur für Molekulare Neurologie
Salvi, Rachele
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Winkler, Jürgen Prof. Dr.
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Xiang, Wei PD Dr.
Lehrstuhl für Biochemie und Molekulare Medizin


Autor(en) der externen Einrichtung(en)
Universidade Nova de Lisboa


Zitierweisen

APA:
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). https://dx.doi.org/10.1038/s41598-018-35811-8

MLA:
Hoffmann, Anna-Carin, et al. "Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose." Scientific Reports 9.1 (2019).

BibTeX: 

Zuletzt aktualisiert 2019-25-03 um 10:38