Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of Parkinson's disease

Academic Article

Abstract

  • © The Author(s) 2018. Published by Oxford University Press. All rights reserved. We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low ( < 1 mM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (> 10 mM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation. We discovered that α-syn expression phenocopies the high iron condition: under the low iron condition ( < 1 mM), α-syn inhibits Snx3-retromer-mediated recycling of Fet3/Ftr1 and instead shunts Fet3/Ftr1 into the multivesicular body pathway to the vacuole. α-Syn inhibits recycling by blocking the association of Snx3-mCherry molecules with endocytic vesicles, possibly by interfering with the binding of Snx3 to phosphatidylinositol-3-monophosphate. In C. elegans, transgenic worms expressing α-syn exhibit an age-dependent degeneration of dopaminergic neurons that is partially rescued by the iron chelator desferoxamine. This implies that α-syn-expressing dopaminergic neurons are susceptible to changes in iron neurotoxicity with age, whereby excess iron enhances α-syn-induced neurodegeneration. In vivo genetic analysis indicates that α-syn dysregulates iron homeostasis in worm dopaminergic neurons, possibly by inhibiting SNX-3-mediated recycling of a membrane-bound ortholog of Cp (F21D5.3), the iron exporter ferroportin (FPN1.1), or both.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Patel D; Xu C; Nagarajan S; Liu Z; Hemphill WO; Shi R; Uversky VN; Caldwell GA; Caldwell KA; Witt SN
  • Start Page

  • 1514
  • End Page

  • 1532
  • Volume

  • 27
  • Issue

  • 9