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

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 (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Autophagy Taylor & Francis

Pages Range: 1-61

DOI: 10.1080/15548627.2017.1395992

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.

Authors with CRIS profile

Georgia Minakaki Professur für Molekulare Neurologie Stefanie Menges Professur für Molekulare Neurologie Iris Schäffner Institut für Biochemie Franz Marxreiter Department of Molecular Neurology Ursula Schlötzer-Schrehardt Medizinische Fakultät Wei Xiang Lehrstuhl für Biochemie und Molekulare Medizin Dieter Chichung Lie Institut für Biochemie Jürgen Winkler Professur für Molekulare Neurologie Jochen Klucken Department of Molecular Neurology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Semmelweis University / Semmelweis Egyetem HU Hungary (HU) University of California, San Diego US United States (USA) (US) Universitätsklinikum Göttingen DE Germany (DE) Ruhr-Universität Bochum (RUB) DE Germany (DE) Academy of Athens / Ακαδημία Αθηνών GR Greece (GR)

How to cite

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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