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Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes

Rostami, Jinar ; Holmqvist, Staffan LU ; Lindström, Veronica ; Sigvardson, Jessica ; Westermark, Gunilla T. ; Ingelsson, Martin ; Bergström, Joakim ; Roybon, Laurent LU and Erlandsson, Anna (2017) In The Journal of Neuroscience 37(49). p.11835-11853
Abstract

Many lines of evidence suggest that the Parkinson’s disease (PD)-related protein α-synuclein (α-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 α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes’ lysosomal digestion of excess α-SYN oligomers results in α-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 α-SYN to healthy astrocytes, which in... (More)

Many lines of evidence suggest that the Parkinson’s disease (PD)-related protein α-synuclein (α-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 α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes’ lysosomal digestion of excess α-SYN oligomers results in α-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 α-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 α-SYN and mitochondria. Together, our results highlight the role of astrocytes in α-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alpha-synuclein, Astrocytes, Lysosomes, Mitochondria, Trans-Golgi, Tunneling nanotubes
in
The Journal of Neuroscience
volume
37
issue
49
pages
19 pages
publisher
Society for Neuroscience
external identifiers
  • scopus:85037644197
  • pmid:29089438
  • wos:000418053700007
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.0983-17.2017
language
English
LU publication?
yes
id
cd05a93f-7443-4712-b1df-1443214bf5d9
date added to LUP
2017-12-21 10:30:04
date last changed
2024-04-15 01:14:56
@article{cd05a93f-7443-4712-b1df-1443214bf5d9,
  abstract     = {{<p>Many lines of evidence suggest that the Parkinson’s disease (PD)-related protein α-synuclein (α-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 α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes’ lysosomal digestion of excess α-SYN oligomers results in α-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 α-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 α-SYN and mitochondria. Together, our results highlight the role of astrocytes in α-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance.</p>}},
  author       = {{Rostami, Jinar and Holmqvist, Staffan and Lindström, Veronica and Sigvardson, Jessica and Westermark, Gunilla T. and Ingelsson, Martin and Bergström, Joakim and Roybon, Laurent and Erlandsson, Anna}},
  issn         = {{0270-6474}},
  keywords     = {{Alpha-synuclein; Astrocytes; Lysosomes; Mitochondria; Trans-Golgi; Tunneling nanotubes}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{49}},
  pages        = {{11835--11853}},
  publisher    = {{Society for Neuroscience}},
  series       = {{The Journal of Neuroscience}},
  title        = {{Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes}},
  url          = {{http://dx.doi.org/10.1523/JNEUROSCI.0983-17.2017}},
  doi          = {{10.1523/JNEUROSCI.0983-17.2017}},
  volume       = {{37}},
  year         = {{2017}},
}