lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed and are posted here as part of a 12-month trial. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

VPS35 Interacts with Dopamine Transportor and Disrupts Dopamine Transporter Recycling Pathway

33 Pages Posted: 16 Jan 2019

See all articles by Yi Huang

Yi Huang

Sun Yat-Sen University (SYSU) - Department of Neurology

Leping Zhou

Sun Yat-Sen University (SYSU) - Department of Neurology

Jiawei Li

National University of Singapore (NUS) - Department of Biological Sciences

Xiang Chen

Sun Yat-Sen University (SYSU) - Department of Neurology

Joseph Thomas

University of Maryland

Xiaofei He

Sun Yat-Sen University (SYSU) - Department of Neurology

Wenyuan Guo

Sun Yat-Sen University (SYSU) - Department of Neurology

Yixuan Zeng

Sun Yat-Sen University (SYSU) - Department of Neurology

Low Boon Chuan

National University of Singapore (NUS) - Department of Biological Sciences

Fengyin Liang

Sun Yat-Sen University (SYSU) - Department of Neurology

Jinsheng Zeng

Sun Yat-Sen University (SYSU) - Department of Neurology

Eng-King Tan

Singapore General Hospital - Department of Neurology; Duke-NUS Graduate Medical School Singapore

Wanli Smith

Johns Hopkins University - Division of Neurobiology

Zhong Pei

Sun Yat-Sen University (SYSU) - Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases

Christopher A. Ross

Johns Hopkins University

More...

Abstract

The exact pathophysiological role of vacuolar protein sorting 35 ortholog (VPS35) in Parkinson's disease (PD) is unknown. Here, we have identified dopaminergic transportor (DAT) as an interacting partner of VPS35. Mutant VPS35 D620N and DAT interaction causes a decrease in membrane DAT by disrupting DAT transport from an early endosome to a recycling endosome via weaker binding to FAM21. The in vitro interactions are further validated in the VPS35-D620N transgenic C. elegans and mice with the AAV-mediated overexpression of VPS35-D620N, which displayed key features of human PD. Our findings identified a novel pathway linking endosomal recycling as a mechanistic link with VPS35 associated PD that could potentially unravel new therapeutic targets.

Funding Statement: The study was partly supported by the grants from: the National Natural Science Foundation of China (No. 81671102, 81873751 ); the National Key Research and Development Program of China, Stem Cell and Translational Research (No. 2017YFA0105104); Guangdong provincial science and technology plan project (No. 2016B030230002, 2017A040406007); Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases; The Southern China International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases (2015B050501003); Guangdong Provincial engineering Center for Major Neurological Disease Treatment.

Declaration of Interests: The authors declare no competing financial interests.

Ethics Approval Statement: Mice were maintained in accordance with institutional guidelines, and all protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the First Affiliated Hospital, Sun Yat-sen University, China.

Keywords: VPS35, DAT, endosomal recycling

Suggested Citation

Huang, Yi and Zhou, Leping and Li, Jiawei and Chen, Xiang and Thomas, Joseph and He, Xiaofei and Guo, Wenyuan and Zeng, Yixuan and Chuan, Low Boon and Liang, Fengyin and Zeng, Jinsheng and Tan, Eng-King and Smith, Wanli and Pei, Zhong and Ross, Christopher A., VPS35 Interacts with Dopamine Transportor and Disrupts Dopamine Transporter Recycling Pathway (January 14, 2019). Available at SSRN: https://ssrn.com/abstract=3315811

Yi Huang

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Leping Zhou

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Jiawei Li

National University of Singapore (NUS) - Department of Biological Sciences

14 Science Drive 4
Singapore, 117543
China

Xiang Chen

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Joseph Thomas

University of Maryland

College Park
College Park, MD 20742
United States

Xiaofei He

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Wenyuan Guo

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Yixuan Zeng

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Low Boon Chuan

National University of Singapore (NUS) - Department of Biological Sciences

Bukit Timah Road 469 G
Singapore, 117591
Singapore

Fengyin Liang

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Jinsheng Zeng

Sun Yat-Sen University (SYSU) - Department of Neurology

Guangzhou, GD 510080
China

Eng-King Tan

Singapore General Hospital - Department of Neurology ( email )

Singapore, 169608
Singapore

Duke-NUS Graduate Medical School Singapore

Singapore
Singapore

Wanli Smith

Johns Hopkins University - Division of Neurobiology ( email )

Baltimore, MD 20036-1984
United States

Zhong Pei (Contact Author)

Sun Yat-Sen University (SYSU) - Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases ( email )

Guangzhou
China

Christopher A. Ross

Johns Hopkins University

Baltimore, MD 20036-1984
United States

Click here to go to TheLancet.com

Go to TheLancet.com

Paper statistics

Abstract Views
292
Downloads
54