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.
Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 308433, Singapore.
Neurobiol Dis. 2021 Jun;153:105313. doi: 10.1016/j.nbd.2021.105313. Epub 2021 Feb 24.
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 Thrand 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.
液泡蛋白分选蛋白 35（VPS35）是参与调节蛋白质运输和回收的逆向转运体复合物的核心组成部分。最近，VPS35（PARK17）中的一个错义突变，天冬氨酸 620 突变为天冬酰胺（D620N），被鉴定为晚发性常染色体显性帕金森病（PD）的致病突变。虽然 PD 的特征是一系列与黑质中多巴胺能神经元丧失相关的运动症状，但在 PD 患者和由多个 PD 相关致病基因（如α-突触核蛋白和富亮氨酸重复激酶 2（LRRK2））引起的 PD 动物模型中，也观察到了非运动症状，如海马神经发生受损。然而，VPS35 D620N 突变在成年海马神经发生中的作用尚不清楚。在这里，我们表明 VPS35 D620N 突变会损害表达 VPS35 D620N 基因的成年转基因小鼠的海马神经发生。具体而言，我们发现神经干细胞池减少，神经增殖和分化减少，迁移延迟，3 个月大的 VPS35 D620N 突变小鼠的神经突生长受损。此外，我们发现 VPS35 D620N 突变体过度磷酸化 APP（淀粉样前体蛋白）在 Thr 和相互作用 APP。值得注意的是，通过将 VPS35 D620N 突变小鼠与 APP 敲除（KO）小鼠杂交，我们发现 APP 功能丧失可挽救 VPS35 D620N 抑制的神经发生、神经迁移和成熟。我们的研究提供了重要证据，表明 APP 参与了 VPS35 D620N 突变调节成年神经发生，这为 PD 的发病机制提供了新的认识。
