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Title: Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP
Authors: Jiang, Mei
Tu, Hai-Tao
Zhang, Ke
Zhang, Wei
Yu, Wei-Ping
Xu, Jie
Tan, Eng-King
Guo, Kai-Hua
Zeng, Li
Keywords: Science::Medicine
Issue Date: 2021
Source: Jiang, M., Tu, H., Zhang, K., Zhang, W., Yu, W., Xu, J., Tan, E., Guo, K. & Zeng, L. (2021). Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP. Neurobiology of Disease, 153, 105313-.
Project: NMRC/OFIRG/0074/2018 
Journal: Neurobiology of Disease 
Abstract: Vacuolar protein sorting protein 35 (VPS35) is a core component of the retromer complex involved in regulating protein trafficking and retrieval. Recently, a missense mutation, Asp620Asn (D620N), in VPS35 (PARK17) has been identified as a pathogenic mutation for late-onset autosomal dominant Parkinson's disease (PD). Although PD is characterized by a range of motor symptoms associated with loss of dopaminergic neurons in the substantial nigra, non-motor symptoms such as impaired hippocampal neurogenesis were observed in both PD patients and animal models of PD caused by multiple PD-linked pathogenic genes such as alpha-synuclein and leucine-rich repeat kinase 2 (LRRK2). However, the role of the VPS35 D620N mutation in adult hippocampal neurogenesis remains unknown. Here, we showed that the VPS35 D620N mutation impaired hippocampal neurogenesis in adult transgenic mice expressing the VPS35 D620N gene. Specifically, we showed a reduction in the neural stem cell pool and neural proliferation and differentiation, retarded migration, and impaired neurite outgrowth in 3-month-old VPS35 D620N mutant mice. Moreover, we found that the VPS35 D620N mutant hyperphosphorylates amyloid precursor protein (APP) at Thr668and interacts with APP. Notably, by crossing the VPS35 D620N mutant mice with APP knockout (KO) mice, we showed that loss of APP function rescues VPS35 D620N-inhibited neurogenesis, neural migration, and maturation. Our study provides important evidence that APP is involved in the VPS35 D620N mutation in regulating adult neurogenesis, which sheds light on the pathogenic mechanisms in PD.
ISSN: 0969-9961
DOI: 10.1016/j.nbd.2021.105313
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: National Neuroscience Institute
Duke-NUS Graduate Medical School
Rights: © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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