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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 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
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alpha-synuclein, Astrocytes, Lysosomes, Mitochondria, Trans-Golgi, Tunneling nanotubes
in
Journal of Neuroscience
volume
37
issue
49
pages
19 pages
publisher
Society for Neuroscience
external identifiers
  • scopus:85037644197
  • 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
2018-04-22 04:34:23
@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},
  keyword      = {Alpha-synuclein,Astrocytes,Lysosomes,Mitochondria,Trans-Golgi,Tunneling nanotubes},
  language     = {eng},
  month        = {12},
  number       = {49},
  pages        = {11835--11853},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0983-17.2017},
  volume       = {37},
  year         = {2017},
}