Mutant VPS35-D620N induces motor dysfunction and impairs DAT-mediated dopamine recycling pathway

Author:

Huang Yi123,Huang Heng1,Zhou Leping1,Li Jiawei4,Chen Xiang1,Thomas Joseph5,He Xiaofei1,Guo Wenyuan1,Zeng Yixuan1,Low Boon Chuan4,Liang Fengyin1,Zeng Jinsheng1,Ross Christopher A6789,Tan Eng-King1011,Smith Wanli1213ORCID,Pei Zhong1ORCID

Affiliation:

1. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology , Guangzhou 510080 , China

2. Center for Reproductive Medicine , Ren Ji Hospital, School of Medicine, , Shanghai 200135 , China

3. Shanghai Jiao Tong University , Ren Ji Hospital, School of Medicine, , Shanghai 200135 , China

4. Department of Biological Sciences, National University of Singapore , Singapore

5. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 Penn Street, Baltimore, MD 21201 , USA

6. Department of Psychiatry and Behavioral Sciences , Division of Neurobiology, , Baltimore, Maryland 21287 , USA

7. Johns Hopkins University School of Medicine , Division of Neurobiology, , Baltimore, Maryland 21287 , USA

8. Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21201 , USA

9. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, Maryland 21201 , USA

10. Department of Neurology , Singapore General Hospital, , Singapore

11. National Neuroscience Institute, Duke-National University of Singapore Graduate Medical School , Singapore General Hospital, , Singapore

12. Department of Psychiatry , Division of Neurobiology, , Baltimore, MD 21287 , USA

13. Johns Hopkins University School of Medicine , Division of Neurobiology, , Baltimore, MD 21287 , USA

Abstract

Abstract The D620N mutation in vacuolar protein sorting protein 35 (VPS35) gene has been identified to be linked to late onset familial Parkinson disease (PD). However, the pathophysiological roles of VPS35-D620N in PD remain unclear. Here, we generated the transgenic Caenorhabditis elegans overexpressing either human wild type or PD-linked mutant VPS35-D620N in neurons. C. elegans expressing VPS35-D620N, compared with non-transgenic controls, showed movement disorders and dopaminergic neuron loss. VPS35-D620N worms displayed more swimming induced paralysis but showed no defects in BSR assays, thus indicating the disruption of dopamine (DA) recycling back inside neurons. Moreover, VPS35 formed a protein interaction complex with DA transporter (DAT), RAB5, RAB11 and FAM21. In contrast, the VPS35-D620N mutant destabilized these interactions, thus disrupting DAT transport from early endosomes to recycling endosomes, and decreasing DAT at the cell surface. These effects together increased DA in synaptic clefts, and led to dopaminergic neuron degeneration and motor dysfunction. Treatment with reserpine significantly decreased the swimming induced paralysis in VPS35-D620N worms, as compared with vehicle treated VPS35-D620N worms. Our studies not only provide novel insights into the mechanisms of VPS35-D620N-induced dopaminergic neuron degeneration and motor dysfunction via disruption of DAT function and the DA signaling pathway but also indicate a potential strategy to treat VPS35-D620N-related PD and other disorders.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases

Guangdong Provincial Clinical Research Center for Neurological Diseases

Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases

Guangdong Provincial Engineering Center for Major Neurological Disease Treatment

Guangzhou Clinical Research and Translational Center for Major Neurological Diseases

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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