Retrograde trafficking of VMAT2 and its role in protein stability in non-neuronal cells

Abstract

Increasing evidence suggests that the impaired neuroprotection of vesicular monoamine transporter 2 (VMAT2) contributes to the pathogenesis of Parkinson's disease. That has been linked to aberrant subcellular retrograde trafficking as strongly indicated by recent genomic studies on familial Parkinson's diseases. However, whether VMAT2 function is regulated by retrograde trafficking is unknown. By using biochemistry and cell biology approaches, we have shown that VMAT2 was stringently localized to the trans-Golgi network and underwent retrograde trafficking in non-neuronal cells. The transporter also interacted with the key component of retromer, Vps35, biochemically and subcellularly. Using specific siRNA, we further showed that Vps35 depletion altered subcellular localization of VMAT2. Moreover, siRNA-mediated Vps35 knockdown also decreased the stability of VMAT2 as demonstrated by the reduced half-life. Thus, our work suggested that altered vesicular trafficking of VMAT2 may play a vital role in neuroprotection of the transporter as well as in the pathogenesis of Parkinson's disease.

Keywords

Parkinson's disease / VMAT2 / Vps35 / retrograde trafficking

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Acknowledgments

This work was supported by the National Nature Science Foundation of China (Grant No.31371436 and No. 8157051134) and by the laboratory start-up grant from Nanjing Medical University to Y. Liu. We also thank Dr. Steven Cheng's lab for the assistance with confocal laser microscopy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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