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Title: Altered striatal dopamine levels in Parkinson's disease VPS35 D620N mutant transgenic aged mice
Authors: Vanan, Sarivin
Zeng, Xiaoxia
Chia, Sook Yoong
Varnäs, Katarina
Jiang, Mei
Zhang, Ke
Saw, Wuan Ting
Padmanabhan, Parasuraman
Yu, Wei-Ping
Zhou, Zhi-Dong
Halldin, Christer
Gulyás, Balázs
Tan, Eng-King
Zeng, Li
Keywords: Science::Medicine
Issue Date: 2020
Source: Vanan, S., Zeng, X., Chia, S. Y., Varnäs, K., Jiang, M., Zhang, K., Saw, W. T., Padmanabhan, P., Yu, W., Zhou, Z., Halldin, C., Gulyás, B., Tan, E. & Zeng, L. (2020). Altered striatal dopamine levels in Parkinson's disease VPS35 D620N mutant transgenic aged mice. Molecular Brain, 13(1).
Project: OFLCG18May-0026
Journal: Molecular Brain
Abstract: Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson's disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.
ISSN: 1756-6606
DOI: 10.1186/s13041-020-00704-3
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Research Centres: Center for Molecular Neuropathology
Rights: © 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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