The clathrin-dependent localization of dopamine transporter to surface membranes is affected by α-Synuclein

Haya Kisos, Tziona Ben-Gedalya, Ronit Sharon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Parkinson's disease (PD) is a progressive age-dependent neurodegenerative disorder, predominantly affecting the dopamine-producing neurons residing at the substantia nigra. Abnormalities in α-synuclein (α-Syn) and dopamine transporter (DAT) are implicated in the pathogenesis of PD. We tested the hypothesis that α-Syn regulates surface DAT localization and DAT activity, in cultured cells co-expressing α-Syn and DAT, and in brains of mice modeling PD, transgenic for the mutant A53T α-Syn form. The results indicate that α-Syn expression affects the partitioning of DAT between the cell surface and intracellular compartments, resulting in lower surface DAT levels. Accordingly, lower uptake of tritiated dopamine was measured in synaptosomes of A53T α-Syn transgenic mouse brains. Importantly, we show that the effect of α-Syn on surface DAT is mediated by clathrin. Downregulation of clathrin by specific siRNAs directed against its heavy chain abolished the effect of α-Syn on phorbol 12-myristate13-acetate-induced DAT internalization. These results suggest that α-Syn plays a role in regulating dopamine homeostasis through its involvement in clathrin-mediated endocytosis.

Original languageAmerican English
Pages (from-to)167-176
Number of pages10
JournalJournal of Molecular Neuroscience
Volume52
Issue number2
DOIs
StatePublished - Feb 2014

Bibliographical note

Funding Information:
Acknowledgments This study was supported by the United States– Israel Binational Science Foundation, grant number 2005102.

Keywords

  • Clathrin-mediated endocytosis
  • Dopamine transporter
  • Parkinson's disease
  • α-Synuclein

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