uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular Geriatrics)
Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Dept Neurol, Pittsburgh, PA 15260 USA.
Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Dept Neurol, Pittsburgh, PA 15260 USA.
Show others and affiliations
2017 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 82, 143-156 p.Article in journal (Refereed) Published
Abstract [en]

The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of α-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic α-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric α-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes. Alpha-synuclein oligomers were found to co-localize with the glial cells and the astrocytes were found to internalize particularly large amounts of the protein. Following ingestion, the astrocytes started to degrade the oligomers via the lysosomal pathway but, due to incomplete digestion, large intracellular deposits remained. Moreover, the astrocytes displayed mitochondrial abnormalities. Taken together, our data indicate that astrocytes play an important role in the clearance of toxic α-synuclein species from the extracellular space. However, when their degrading capacity is overburdened, α-synuclein deposits can persist and result in detrimental cellular processes.

Place, publisher, year, edition, pages
2017. Vol. 82, 143-156 p.
Keyword [en]
Astrocytes, Glia, Mitochondria, Oligodendrocytes, Parkinson's disease, α-Synuclein oligomers
National Category
Other Medical Sciences
Research subject
Medical Science; Biology with specialization in Molecular Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-326114DOI: 10.1016/j.mcn.2017.04.009ISI: 000405977400015PubMedID: 28450268OAI: oai:DiVA.org:uu-326114DiVA: diva2:1118809
Funder
Swedish Research Council, 2015-02671Magnus Bergvall Foundation, 2016-01714Marianne and Marcus Wallenberg FoundationThe Swedish Brain Foundation
Available from: 2017-07-02 Created: 2017-07-02 Last updated: 2017-11-29Bibliographically approved
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)
Opponent
Supervisors
Available from: 2017-08-23 Created: 2017-07-05 Last updated: 2017-09-08

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Lindström, VeronicaGustafsson, GabrielIngelsson, MartinBergström, JoakimErlandsson, Anna

Search in DiVA

By author/editor
Lindström, VeronicaGustafsson, GabrielIngelsson, MartinBergström, JoakimErlandsson, Anna
By organisation
Geriatrics
In the same journal
Molecular and Cellular Neuroscience
Other Medical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 204 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf