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Autophagy. 2018;14(1):98-119. doi: 10.1080/15548627.2017.1395992. Epub 2018 Jan 15.

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

Author information

1
a Department of Molecular Neurology , University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) , Erlangen , Germany.
2
b Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences , Semmelweis University , Budapest , Hungary.
3
c Department of Neuroscience, Center for Basic Research , Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
4
d Institute of Biochemistry , FAU , Erlangen , Germany.
5
e Medizinisches Proteom-Center, Medical Faculty , Ruhr University Bochum , Bochum , Germany.
6
f Department of Neurosciences , University of California , San Diego , CA USA.
7
g Paracelsus-Elena-Klinik, Kassel and Departments of Neuropathology & Neurosurgery , & University Medical Center , Göttingen.
8
h Department of Genetics, Cell and Immunobiology , Semmelweis University , Budapest , Hungary.
9
i Department of Opthalmology University Hospital Erlangen , Erlangen , Germany.
10
j Department of Pathology , University of California , San Diego , CA USA.

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.

KEYWORDS:

Parkinson disease; SNCA; alpha-synuclein; autophagosome; cell-to-cell transfer; cerebrospinal fluid; dementia with Lewy bodies; extracellular vesicles; multivesicular body; release; synucleinopathies

PMID:
29198173
PMCID:
PMC5846507
DOI:
10.1080/15548627.2017.1395992
[Indexed for MEDLINE]
Free PMC Article

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