Journal
AUTOPHAGY
Volume 14, Issue 1, Pages 98-119Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2017.1395992
Keywords
alpha-synuclein; autophagosome; cell-to-cell transfer; cerebrospinal fluid; dementia with Lewy bodies; extracellular vesicles; multivesicular body; Parkinson disease; release; SNCA; synucleinopathies
Categories
Funding
- Interdisciplinary Center of Clinical Research (IZKF) of the University Hospital Erlangen, Germany (IZKF) [E21, E11]
- Johannes und Frieda Marohn-Stiftung (Alpha-synuclein)
- deutsche Forschungsgemeinschaft/German Research Foundation (DFG) [KL1395/ 8-1]
- Research Foundation Medicine, University Hospital Erlangen (Parkinson and Nutrition)
- Bavarian State Ministry of Education and Culture, Science and Arts
- National Institutes of Health (NIH) [NIH AGO5131, NIH AG18440]
- P.U.R.E., Protein Unit for Research in Europe, North Rhine-Westphalia
- H2020 project NISCI [681094]
- NATIONAL INSTITUTE ON AGING [ZIAAG000936] Funding Source: NIH RePORTER
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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/auto phagy may regulate EV protein composition and consequently progression in synucleinopathies.
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