Ginkgolide K promotes the clearance of A53T mutation alpha-synuclein in SH-SY5Y cells

Cell Biol Toxicol. 2018 Aug;34(4):291-303. doi: 10.1007/s10565-017-9419-4. Epub 2017 Dec 6.

Abstract

Alpha-synuclein (α-syn) is associated to Parkinson's disease (PD). The aggregated form of α-syn has potential neurotoxicity. Thus, the clearance of α-syn aggregation is a plausible strategy to delay disease progression of PD. In our study, we found that the treatment of Ginkgolide B (GB) and Ginkgolide K (GK) reduced cell death, and enhanced cell proliferation in SH-SY5Y cells, which overexpressed A53T mutant α-syn. Surprisingly, GK, but not GB, promoted the clearance of A53T α-syn, which can be abolished by autophagy inhibitor 3-methyladenine, indicating that GK-induced autophagy intervened in the clearance of A53T α-syn. However, GK did not affect the NEDD4 that belongs to the ubiquitin ligase in the endosomal-lysosomal pathway. Furthermore, GK treatment inhibited the p-NF-kB/p65 and induced the PI3K, BDNF, and PSD-95. Taken together, GK increased the clearance of α-syn, reduced cell death, and triggered complex crosstalk between different signaling pathways. Although our results show a potentially new therapeutic candidate for PD, the details of this mechanism need to be further identified.

Keywords: Alpha-synuclein; Autophagy; Ginkgolide B; Ginkgolide K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Line, Tumor
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Frizzled Receptors / metabolism
  • Ginkgolides / pharmacology*
  • Humans
  • Lactones / pharmacology*
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Mutation / genetics*
  • Neuroprotective Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Synapses / metabolism
  • Up-Regulation / drug effects
  • Wnt Proteins / metabolism
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / toxicity
  • beta Catenin / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Frizzled Receptors
  • Ginkgolides
  • Lactones
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Neuroprotective Agents
  • Wnt Proteins
  • alpha-Synuclein
  • beta Catenin
  • ginkgolide K
  • ginkgolide B