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Secretion and uptake of α-synuclein via extracellular vesicles in cultured cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Molecular geriatrics)
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(English)Manuscript (preprint) (Other academic)
National Category
Other Medical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-326117OAI: oai:DiVA.org:uu-326117DiVA: diva2:1120246
Available from: 2017-07-05 Created: 2017-07-05 Last updated: 2017-07-05
In thesis
1. Alpha-Synuclein Oligomers: Cellular Mechanisms and Aspects of Antibody Treatment
Open this publication in new window or tab >>Alpha-Synuclein Oligomers: Cellular Mechanisms and Aspects of Antibody Treatment
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), aggregated α-synuclein deposit inside cells within the brain. Smaller soluble α-synuclein aggregates, oligomers, are present both intra- and extracellularly. The α-synuclein oligomers are known to be particularly harmful, although the underlying neurotoxic mechanisms are not fully understood. The aim of this thesis was to investigate the pathogenic roles of α-synuclein oligomers and the possibility to target such species with antibody treatment.

Passive immunotherapy with α-synuclein antibodies can lead to reduced pathology and ameliorated symptoms in transgenic mice. However, it remains unknown whether the antibodies are taken up by cells or whether they act extracellularly. In Paper I, we assessed cellular internalization of various α-synuclein monoclonal antibodies. The oligomer selective mAb47 displayed the highest uptake, which was promoted by the extracellular presence of α-synuclein.

Alpha-synuclein aggregates can be found in both neurons and glial cells, but the pathogenic role of glial deposits has only been sparsely investigated. In Paper II, co-cultures of neurons and glia were exposed to α-synuclein oligomers. The astrocytes in the cultures rapidly accumulated oligomers, which were only partially degraded by lysosomes. The sustained intracellular α-synuclein deposits were associated with mitochondrial stress reactions in the astrocytes. 

In Paper III, we sought to explore whether the astrocytic pathology induced by α-synuclein oligomers could be ameliorated by antibody treatment. Pre-incubation of oligomers with mAb47 promoted α-synuclein clearance, reduced astrocytic accumulation and rescued cells from mitochondrial stress. We could demonstrate that binding of the antibody to its antigen in the extracellular space was crucial for these effects to occur.

The progressive pathology in PD is believed to be driven by cell-to-cell spreading of α-synuclein aggregates, potentially via exosomes and other extracellular vesicles (EVs). In Paper IV, we found that either fusing α-synuclein to a non-physiological protein tag or introducing the PD-causing A53T mutation directed α-synuclein towards EV secretion. Also, EV-associated α-synuclein was particularly prone to induce toxicity in recipient cells.

In conclusion, this thesis sheds new light on the cellular dysfunction related to α-synuclein pathology and on how the underlying pathogenic processes may be targeted by antibody treatment.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1344
Keyword
Parkinson's Disease, Alpha-synuclein, Aggregation, Oligomers, Monoclonal Antibody, Glia, Astrocyte, Immunofluorescence
National Category
Other Medical Sciences not elsewhere specified
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-326320 (URN)978-91-513-0008-5 (ISBN)
Public defence
2017-09-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2017-08-23 Created: 2017-07-05 Last updated: 2017-09-08

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