Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autor(en): Minakaki G, Menges S, Kittel A, Emmanouilidou E, Schäffner I, Barkovits K, Bergmann A, Rockenstein E, Adame A, Marxreiter F, Mollenhauer B, Galasko D, Buzás EI, Schlötzer-Schrehardt U, Marcus K, Xiang W, Lie DC, Vekrellis K, Masliah E, Winkler J, Klucken J
Zeitschrift: Autophagy
Jahr der Veröffentlichung: 2017
Seitenbereich: 1-61
ISSN: 1554-8627


Abstract


The autophagy-lysosome pathway (ALP) regulates intracellular homeostasis of the cytosolic protein SNCA/alpha-synuclein and is impaired in synucleinopathies, including Parkinson disease and dementia with Lewy bodies (DLB). Emerging evidence suggests that ALP influences SNCA release, but the underlying cellular mechanisms are not well understood. Several studies identified SNCA in exosome/extracellular vesicle (EV) fractions. EVs are generated in the multivesicular body compartment and either released upon its fusion with the plasma membrane, or cleared via the ALP. We therefore hypothesized that inhibiting ALP clearance 1) enhances SNCA release via EVs by increasing extracellular shuttling of multivesicular body contents, 2) alters EV biochemical profile, and 3) promotes SNCA cell-to-cell transfer. Indeed, ALP inhibition increased the ratio of extra- to intracellular SNCA and upregulated SNCA association with EVs in neuronal cells. Ultrastructural analysis revealed a widespread, fused multivesicular body-autophagosome compartment. Biochemical characterization revealed the presence of autophagosome-related proteins, such as LC3-II and SQSTM1. This distinct "autophagosome-exosome-like" profile was also identified in human cerebrospinal fluid (CSF) EVs. After a single intracortical injection of SNCA-containing EVs derived from CSF into mice, human SNCA colocalized with endosome and neuronal markers. Prominent SNCA immunoreactivity and a higher number of neuronal SNCA inclusions were observed after DLB patient CSF EV injections. In summary, this study provides compelling evidence that a) ALP inhibition increases SNCA in neuronal EVs, b) distinct ALP components are present in EVs, and c) CSF EVs transfer SNCA from cell to cell in vivo. Thus, macroautophagy/autophagy may regulate EV protein composition and consequently progression in synucleinopathies.



FAU-Autoren / FAU-Herausgeber

Klucken, Jochen Prof. Dr.
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Lie, Dieter Chichung Prof. Dr.
Institut für Biochemie
Marxreiter, Franz Dr. med.
Molekular-Neurologische Abteilung in der Neurologischen Klinik
Menges, Stefanie
Professur für Molekulare Neurologie
Minakaki, Georgia
Professur für Molekulare Neurologie
Schäffner, Iris Dr.
Institut für Biochemie
Schlötzer-Schrehardt, Ursula apl. Prof. Dr.
Medizinische Fakultät
Winkler, Jürgen Prof. Dr.
Professur für Molekulare Neurologie
Xiang, Wei PD Dr.
Lehrstuhl für Biochemie und Molekulare Medizin


Autor(en) der externen Einrichtung(en)
Academy of Athens / Ακαδημία Αθηνών
Ruhr-Universität Bochum (RUB)
Semmelweis University
Universitätsklinikum Göttingen
University of California, San Diego


Zitierweisen

APA:
Minakaki, G., Menges, S., Kittel, A., Emmanouilidou, E., Schäffner, I., Barkovits, K.,... Klucken, J. (2017). Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy, 1-61. https://dx.doi.org/10.1080/15548627.2017.1395992

MLA:
Minakaki, Georgia, et al. "Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype." Autophagy (2017): 1-61.

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Zuletzt aktualisiert 2018-08-10 um 08:31