Enhancing the Astrocytic Clearance of Extracellular α-Synuclein Aggregates by Ginkgolides Attenuates Neural Cell Injury

Cell Mol Neurobiol. 2019 Oct;39(7):1017-1028. doi: 10.1007/s10571-019-00696-2. Epub 2019 Jun 5.

Abstract

The accumulation of aggregated forms of the α-Synuclein (α-Syn) is associated with the pathogenesis of Parkinson's disease (PD), and the efficient clearance of aggregated α-Syn represents a potential approach in PD therapy. Astrocytes are the most numerous glia cells in the brain and play an essential role in supporting brain functions in PD state. In the present study, we demonstrated that cultured primary astrocytes engulfed and degraded extracellular aggregated recombinant human α-Syn. Meanwhile, we observed that the clearance of α-Syn by astrocytes was abolished by proteasome inhibitor MG132 and autophagy inhibitor 3-methyladenine (3MA). We further showed that intracellular α-Syn was reduced after ginkgolide B (GB) and bilobalide (BB) treatment, and the decrease was reversed by MG132 and 3MA. More importantly, GB and BB reduced indirect neurotoxicity to neurons induced by α-Syn-stimulated astrocytic conditioned medium. Together, we firstly find that astrocytes can engulf and degrade α-Syn aggregates via the proteasome and autophagy pathways, and further show that GB and BB enhance astrocytic clearance of α-Syn, which gives us an insight into the novel therapy for PD in future.

Keywords: Astrocytes; Autophagy; Bilobalide; Ginkgolide B; α-Synuclein.

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology*
  • Autophagy / drug effects
  • Cell Line, Tumor
  • Culture Media, Conditioned / pharmacology
  • Cyclopentanes / pharmacology
  • Endocytosis / drug effects
  • Extracellular Space / chemistry*
  • Furans / pharmacology
  • Ginkgolides / pharmacology*
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Aggregates*
  • Proteolysis / drug effects
  • Recombinant Proteins / metabolism
  • Ubiquitin / metabolism
  • alpha-Synuclein / metabolism*

Substances

  • Culture Media, Conditioned
  • Cyclopentanes
  • Furans
  • Ginkgolides
  • Protein Aggregates
  • Recombinant Proteins
  • Ubiquitin
  • alpha-Synuclein
  • Proteasome Endopeptidase Complex
  • bilobalide