Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP
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 Parkins...
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sg-ntu-dr.10356-1606352023-03-05T16:51:16Z Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP Jiang, Mei Tu, Hai-Tao Zhang, Ke Zhang, Wei Yu, Wei-Ping Xu, Jie Tan, Eng-King Guo, Kai-Hua Zeng, Li Lee Kong Chian School of Medicine (LKCMedicine) National Neuroscience Institute Duke-NUS Graduate Medical School Science::Medicine Adult Neurogenesis Migration 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. National Medical Research Council (NMRC) Published version This work was supported by the Open Fund-Individual Research Grant of National Medical Research Council of Singapore to L. Zeng (No. NMRC/OFIRG/0074/2018), the International Program for Ph.D. Candidates of Sun Yat-Sen University, the Science and Technology Planning Project of Guangzhou (No.202002030441), and the Natural Science Foundation of Guangdong Province, China (No.2019A1515011184 and 2020A1515010012). 2022-07-29T01:42:30Z 2022-07-29T01:42:30Z 2021 Journal Article 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-. https://dx.doi.org/10.1016/j.nbd.2021.105313 0969-9961 https://hdl.handle.net/10356/160635 10.1016/j.nbd.2021.105313 33636388 2-s2.0-85101904766 153 105313 en NMRC/OFIRG/0074/2018 Neurobiology of Disease © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
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Science::Medicine Adult Neurogenesis Migration Jiang, Mei Tu, Hai-Tao Zhang, Ke Zhang, Wei Yu, Wei-Ping Xu, Jie Tan, Eng-King Guo, Kai-Hua Zeng, Li Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP |
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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. |
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Lee Kong Chian School of Medicine (LKCMedicine) |
author_facet |
Lee Kong Chian School of Medicine (LKCMedicine) Jiang, Mei Tu, Hai-Tao Zhang, Ke Zhang, Wei Yu, Wei-Ping Xu, Jie Tan, Eng-King Guo, Kai-Hua Zeng, Li |
format |
Article |
author |
Jiang, Mei Tu, Hai-Tao Zhang, Ke Zhang, Wei Yu, Wei-Ping Xu, Jie Tan, Eng-King Guo, Kai-Hua Zeng, Li |
author_sort |
Jiang, Mei |
title |
Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP |
title_short |
Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP |
title_full |
Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP |
title_fullStr |
Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP |
title_full_unstemmed |
Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP |
title_sort |
impaired neurogenesis in the hippocampus of an adult vps35 mutant mouse model of parkinson's disease through interaction with app |
publishDate |
2022 |
url |
https://hdl.handle.net/10356/160635 |
_version_ |
1759855751017267200 |