Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 49, Pages 11835-11853Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0983-17.2017
Keywords
alpha-synuclein; astrocytes; lysosomes; mitochondria; trans-Golgi; tunneling nanotubes
Categories
Funding
- Swedish Research Council
- Parkinson Foundation
- Alzheimer Foundation
- Ahlen Foundation
- Dementia Association Foundation
- Crafoord Foundation
- Kockska Foundation
- Ake Wiberg Foundation
- Lennart and Christina Kalen, Hedlunds Foundation
- Brain Stem-Stem Cell Center of Excellence in Neurology - Innovation Fund Denmark
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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.
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