Synucleins Antagonize Endoplasmic Reticulum Function to Modulate Dopamine Transporter Trafficking |
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| Authors: | Adam W Oaks Nicholas Marsh-Armstrong Jessica M Jones Joel J Credle Anita Sidhu |
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| Institution: | 1. Laboratory of Molecular Neurochemistry, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, D.C., United States of America.; 2. The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; 3. Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, United States of America.; Ludwig Maximilians University Munich, Germany, |
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| Abstract: | Synaptic re-uptake of dopamine is dependent on the dopamine transporter (DAT), which is regulated by its distribution to the cell surface. DAT trafficking is modulated by the Parkinson''s disease-linked protein alpha-synuclein, but the contribution of synuclein family members beta-synuclein and gamma-synuclein to DAT trafficking is not known. Here we use SH-SY5Y cells as a model of DAT trafficking to demonstrate that all three synucleins negatively regulate cell surface distribution of DAT. Under these conditions the synucleins limit export of DAT from the endoplasmic reticulum (ER) by impairment of the ER-Golgi transition, leading to accumulation of DAT in this compartment. This mechanism for regulating DAT export indirectly through effects on ER and Golgi function represents a previously unappreciated role for the extended synuclein family that is likely applicable to trafficking of the many proteins that rely on the secretory pathway. |
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