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  3. Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP

Impaired neurogenesis in the hippocampus of an adult VPS35 mutant mouse model of Parkinson's disease through interaction with APP

  • Neurobiol Dis. 2021 Jun;153:105313. doi: 10.1016/j.nbd.2021.105313.
Mei Jiang 1,  Hai-Tao Tu 2,  Ke Zhang 2,  Wei Zhang 2,  Wei-Ping Yu 3,  Jie Xu 4,  Eng-King Tan 5,  Kai-Hua Guo 6,  Li Zeng 7
Affiliations

Affiliations

  • 1 Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 308433, Singapore; Department of Neurobiology and Anatomy, Sun Yat-Sen University Zhongshan School of Medicine, 74 Zhongshan 2nd Road, Guangzhou 510089, PR China.
  • 2 Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 308433, Singapore.
  • 3 Animal Gene Editing Laboratory, Biological resource Centre, A*STAR, 138673, Singapore; Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, 138673, Singapore.
  • 4 Department of Neurobiology and Anatomy, Sun Yat-Sen University Zhongshan School of Medicine, 74 Zhongshan 2nd Road, Guangzhou 510089, PR China; Guangdong Province Key Laboratory of Brain Function and disease, Sun Yat-Sen University Zhongshan School of Medicine, 74 Zhongshan 2nd Road, Guangzhou 510089, PR China.
  • 5 Department of Neurology, National Neuroscience Institute, SGH Campus, 169856, Singapore; Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, 169857, Singapore. Electronic address: tan.eng.king@singhealth.com.sg.
  • 6 Department of Neurobiology and Anatomy, Sun Yat-Sen University Zhongshan School of Medicine, 74 Zhongshan 2nd Road, Guangzhou 510089, PR China; Guangdong Province Key Laboratory of Brain Function and disease, Sun Yat-Sen University Zhongshan School of Medicine, 74 Zhongshan 2nd Road, Guangzhou 510089, PR China. Electronic address: guokh@mail.sysu.edu.cn.
  • 7 Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 308433, Singapore; Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, 169857, Singapore; Lee Kong Chian School of Medicine, Nanyang Technology University, Novena Campus, 11 Mandalay Road, 308232, Singapore. Electronic address: Li_Zeng@nni.com.sg.
PMID: 33636388 DOI: 10.1016/j.nbd.2021.105313
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.

Keywords

APP; Adult neurogenesis; Migration; Neurite outgrowth; VPS35-D620N mutation.

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