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<p>The intercellular transmission of α-synuclein contributes to Parkinson’s disease pathology. Yet, the mechanisms of α-synuclein spread are not fully understood. Here we used live-cell microscopy to examine the impact of Parkinson’s disease associated lipid alterations on α-synuclein release. We discovered that increased glucosylceramides as a consequence of reduced β-glucocerebrosidase activity induce ectosome shedding from primary neurons and from dopaminergic neurons derived from induced pluripotent stem cells of a patient with Parkinson’s disease harbouring mutations in <i>GBA1</i> (N370S, L444P and W378G) and <i>LRRK2</i> (G2019S and R1441H) compared with their isogenic control. We show that elevated glucosylceramide and the pharmacological inhibition of β-glucocerebrosidase similarly increase vesicle release and uptake by other neurons in mouse brains. Finally, we show that ectosomes are loaded with α-synuclein and lead to the transmission of α-synuclein pathology to neighbouring neurons. These data reveal ectosomes as a major route for α-synuclein transmission in Parkinson’s disease.</p>

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Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson’s disease

  • 期刊论文

  • 发表日期：

    2026年2月12日

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  • Julie Jacquemyn,
  • Brian Marriott,
  • Jinlan Chang,
  • Ehlam Iftikhar,
  • Kennedi Chik,
  • Nathanael Y. J. Lee,
  • Luis F. Rubio Atonal,
  • Ceili Green,
  • Jeremy Wong,
  • Claudia Acevedo-Morantes,
  • Carol X.-Q. Chen,
  • Michael Nicouleau,
  • Zhipeng You,
  • Eric Deneault,
  • Narges Abdian,
  • Thomas M. Durcan,
  • Jesse Jackson,
  • Maria S. Ioannou

摘要

The intercellular transmission of α-synuclein contributes to Parkinson’s disease pathology. Yet, the mechanisms of α-synuclein spread are not fully understood. Here we used live-cell microscopy to examine the impact of Parkinson’s disease associated lipid alterations on α-synuclein release. We discovered that increased glucosylceramides as a consequence of reduced β-glucocerebrosidase activity induce ectosome shedding from primary neurons and from dopaminergic neurons derived from induced pluripotent stem cells of a patient with Parkinson’s disease harbouring mutations in GBA1 (N370S, L444P and W378G) and LRRK2 (G2019S and R1441H) compared with their isogenic control. We show that elevated glucosylceramide and the pharmacological inhibition of β-glucocerebrosidase similarly increase vesicle release and uptake by other neurons in mouse brains. Finally, we show that ectosomes are loaded with α-synuclein and lead to the transmission of α-synuclein pathology to neighbouring neurons. These data reveal ectosomes as a major route for α-synuclein transmission in Parkinson’s disease.