Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes
(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
- Rostami, Jinar ; Holmqvist, Staffan LU ; Lindström, Veronica ; Sigvardson, Jessica ; Westermark, Gunilla T. ; Ingelsson, Martin ; Bergström, Joakim ; Roybon, Laurent LU and Erlandsson, Anna
- organization
- publishing date
- 2017-12-06
- 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
- 2025-02-05 09:17:29
@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}}, }