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Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Molekylär geriatrik/Rudbäcklaboratoriet)
Lund Univ, Wallenberg Neurosci Ctr, Stem Cell Lab CNS Dis Modeling, Dept Expt Med Sci, S-22184 Lund, Sweden.;Lund Univ, Strateg Res Area MultiPk, S-22184 Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molekylär geriatrik/Rudbäcklaboratoriet)
BioArctic AB, S-11251 Stockholm, Sweden..
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2017 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 49, p. 11835-11853Article in journal (Refereed) Published
Abstract [en]

Many lines of evidence suggest that the Parkinson's disease (PD)-related protein alpha-synuclein (alpha-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated alpha-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess alpha-SYN oligomers results in alpha-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of alpha-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both alpha-SYN and mitochondria. Together, our results highlight the role of astrocytes in alpha-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.

Place, publisher, year, edition, pages
SOC NEUROSCIENCE , 2017. Vol. 37, no 49, p. 11835-11853
Keyword [en]
alpha-synuclein, astrocytes, lysosomes, mitochondria, trans-Golgi, tunneling nanotubes
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-340258DOI: 10.1523/JNEUROSCI.0983-17.2017ISI: 000418053700007PubMedID: 29089438OAI: oai:DiVA.org:uu-340258DiVA: diva2:1179233
Funder
Swedish Research CouncilThe Crafoord FoundationÅke Wiberg Foundation
Available from: 2018-01-31 Created: 2018-01-31 Last updated: 2018-01-31Bibliographically approved

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Rostami, JinarWestermark, GunillaIngelsson, MartinBergström, JoakimErlandsson, Anna
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