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Investigation of Endocytic Pathways for the Internalization of Exosome-Associated Oligomeric Alpha-Synuclein.

ABSTRACT: Misfolding and aggregation of alpha-synuclein (?syn) resulting in cytotoxicity is a hallmark of Parkinson's disease (PD) and related synucleinopathies. The recent body of evidence indicates that ?syn can be released from neuronal cells by nonconventional exocytosis involving extracellular vesicles (EVs) such as exosomes. The transfer of ?syn between cells has been proposed to be an important mechanism of disease propagation in PD. To date, exosome trafficking mechanisms, including release and cell-cell transmission, have not been fully described. To gain insight into the mechanisms involved, exosomes were purified from conditioned media of stable cells secreting ?syn oligomers. A novel bimolecular protein complementation assay was used to detect exosomes containing ?syn oligomers. Recipient cells were treated with exosomes containing ?syn oligomers or "free" non-exosome-associated ?syn oligomers and internalization was monitored. We demonstrate that cell-derived exosome-associated ?syn oligomers can be efficiently internalized by recipient cells. Interestingly exosome-free ?syn oligomers isolated from conditioned medium were not internalized but remained bound to the extracellular surface. To investigate the endocytic pathway(s) required for the exosome uptake different pharmacological inhibitors of caveolin-dependent, clathrin-dependent, and macropinocytosis pathways were utilized. Surprisingly, none of these pathways appear to play a significant role in the internalization of exosome-associated ?syn oligomers. Finally, the role of heparin sulfate proteoglycans (HSPGs) in exosome-associated ?syn internalization was investigated using genetic approach. Despite previous studies showing HSPGs can modulate internalization of fibrillar ?syn, genetic manipulations did not attenuate internalization of exosome-associated ?syn oligomers in our hands, suggesting that exosome-associated ?syn is internalized via an alternative endocytic pathway(s) that has yet to be elucidated.

SUBMITTER: Delenclos M

PROVIDER: S-EPMC5371652 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Investigation of Endocytic Pathways for the Internalization of Exosome-Associated Oligomeric Alpha-Synuclein.

Delenclos Marion M Trendafilova Teodora T Mahesh Divya D Baine Ann M AM Moussaud Simon S Yan Irene K IK Patel Tushar T McLean Pamela J PJ

Frontiers in neuroscience 20170330

Misfolding and aggregation of alpha-synuclein (αsyn) resulting in cytotoxicity is a hallmark of Parkinson's disease (PD) and related synucleinopathies. The recent body of evidence indicates that αsyn can be released from neuronal cells by nonconventional exocytosis involving extracellular vesicles (EVs) such as exosomes. The transfer of αsyn between cells has been proposed to be an important mechanism of disease propagation in PD. To date, exosome trafficking mechanisms, including release and ce ...[more]

PMID: 28424577

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Project description:Background: Little is known about the underlying mechanisms of the similarities in the core features of postoperative delirium (POD) and α-synuclein (α-syn)-related cognitive disorders. We herein investigated associations between fluctuated levels of exosomal α-syn in the plasma and POD presentation in geriatric hip fracture patients. Methods: We conducted an observational, prospective, and 1:1 matched (on age older than 65, hip fracture diagnosis, American Society of Anesthesiologist' (ASA) physical status, duration of surgery, and intraoperative bleeding) case-control study: POD cases and non-POD controls were selected from the overall cohort by using Confusion Assessment Method (CAM). Delirium severity was measured by the Memorial Delirium Assessment Scale (MDAS). Plasma exosome levels of α-syn were examined preoperatively and at the time that POD was diagnosed, by using an established immunocapture technology based on a putative brain-cell-specific marker. Circulating concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also determined. The relationship between α-syn levels and POD risk, as well as the association between α-syn and MDAS scores and plasma cytokines, were assessed. Results: POD incidence was 8.4% (17/202). Postoperative α-syn were either elevated or lowered. As primary outcome variables, the change of α-syn in POD patients was significantly higher than non-POD ones (21.0 ± 29.3 pg.ml-1 vs.1.9 ± 20.0, P = 0.047). The α-syn alteration was positively correlated to MDAS (r = 0.436, P = 0.010) and the change of IL-6 (r = 0.383, P = 0.025). Conclusions: Exosome α-syn release in plasma may be associated with the POD development which might be due to systemic inflammation. Clinical Trial Registration: www.clinicaltrials.gov, identifier ChiCTR-IPR-17012301. Prior Presentation: The abstract of this work has been selected for presentation in the 2019 ANESTHESIOLOGY Journal Symposium "What's New with the old," and it has been present in the ASA 2019 annual meeting October 21st, 2019 in Florida.

Dataset Information

Investigation of Endocytic Pathways for the Internalization of Exosome-Associated Oligomeric Alpha-Synuclein.

Publications

Investigation of Endocytic Pathways for the Internalization of Exosome-Associated Oligomeric Alpha-Synuclein.

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