Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Jinar Rostami
  • Staffan Holmqvist
  • Veronica Lindström
  • Jessica Sigvardson
  • Gunilla T. Westermark
  • Martin Ingelsson
  • Joakim Bergström
  • Laurent Roybon
  • Anna Erlandsson
Organisations
External organisations
  • Uppsala University
  • BioArctic AB
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Alpha-synuclein, Astrocytes, Lysosomes, Mitochondria, Trans-Golgi, Tunneling nanotubes
Original languageEnglish
Pages (from-to)11835-11853
Number of pages19
JournalJournal of Neuroscience
Volume37
Issue number49
Publication statusPublished - 2017 Dec 6
Publication categoryResearch
Peer-reviewedYes