Dysregulated trafficking of the ?-amyloid precursor protein (APP) and glutamate receptors contributes to the pathogenesis/pathology of Alzheimer's disease (AD). The SorL1 protein interacts with APP and changes in SorL1 expression or function affects the subcellular distribution and thus the processing of APP. The retromer complex is composed of VPS35, VPS29, VPS26 and Sorting Nexins 1 and 2, and regulates retrograde sorting from the endosome to the trans-Golgi network (TGN). Deficits in retromer transport are implicated in sporadic AD but most studies propose a link between the retromer complex and ?-secretase (BACE1) transport. Although VPS35 and VPS26 interact with SorL1, how retromer regulates APP trafficking and processing is largely unknown. Sorting Nexin 27 (SNX27) belongs to the Sorting Nexin family whose members regulate protein endocytosis and recycling. Our recent findings published in Nature Medicine demonstrate that SNX27 directly mediates glutamate receptor sorting to the plasma membrane, and attenuated SNX27 expression in Down syndrome (DS) brain contributes to synaptic dysfunction and neurodegeneration. Significantly, we find that SNX27 re-expression can ameliorate neuropathological and behavioral phenotypes in a DS mouse model. We attempt to further establish molecular mechanisms underlying SNX27-mediated neurodegeneration through the trafficking and homeostasis of glutamate receptors and APP. Our preliminary results indicate that SNX27 interacts with VPS26 and VPS35, components of the retromer complex. In addition, we find that SNX27 regulated cell surface glutamate receptor levels in a retromer-dependent manner and downregulation of VPS26 or VPS35 abolished the effect of SNX27 overexpression on promoting cell surface levels of glutamate receptors. Additionally, we find that overexpression and downregulation of SNX27 reduced and increased A? levels, respectively, further suggesting that SNX27 can also regulate trafficking and processing of APP. Our results also show that SNX27-mediated APP trafficking potentially occurs through direct interactions with the APP trafficking receptor SorL1 since overexpression and downregulation of SNX27 can increase and decrease SorL1 levels, respectively. Therefore, we hypothesize that interactions between SNX27, SorL1 and the retromer complex play important roles in AD by coordinating APP endocytic and golgi retromer trafficking pathways that attenuate A? generation, and by maintaining proper cell surface homeostasis of glutamate receptors. In this proposal, we will ascertain whether SNX27, SorL1 and the retromer complex coordinately regulate APP trafficking/processing and cell surface homeostasis of glutamate receptors and synaptic function. Moreover, as deficiencies in VPS35 and SorL1 may accelerate onset of disease-like phenotypes in AD mice, we will study whether overexpression of SNX27 can delay early-onset neuropathological and cognitive phenotypes in AD mice bearing VPS35- or SorL1-haploinsufficiencies.

Public Health Relevance

Dysregulation of intracellular trafficking of APP and glutamate receptors may promote A generation and impair synaptic functions, thus contributing to the pathogenesis/pathology of Alzheimer's disease (AD). Our preliminary results suggest that SNX27, SorL1 and retromer interact with each other and coordinately regulate the retrograde transport of APP and the cell surface recycling of glutamate receptors;further ascertaining the role of SNX27-SorL1-retromer in AD and elucidating the underlying pathways will not only reveal new mechanisms responsible for disease pathogenesis/pathology, but also provide new targets for disease intervention.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS046673-11
Application #
8722900
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yan, Li; Chen, Yaomin; Li, Wubo et al. (2016) RPS23RG1 reduces Aβ oligomer-induced synaptic and cognitive deficits. Sci Rep 6:18668
Zheng, Qiuyang; Zheng, Xiaoyuan; Zhang, Lishan et al. (2016) The Neuron-Specific Protein TMEM59L Mediates Oxidative Stress-Induced Cell Death. Mol Neurobiol :
Wang, Chen; Niu, Mengxi; Zhou, Zehua et al. (2016) VPS35 regulates cell surface recycling and signaling of dopamine receptor D1. Neurobiol Aging 46:22-31
Huang, Timothy Y; Zhao, Yingjun; Li, Xiaoguang et al. (2016) SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein. J Neurosci 36:7996-8011
Barini, Erica; Antico, Odetta; Zhao, Yingjun et al. (2016) Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol Neurodegener 11:16
Zhang, Cuilin; Shi, Zhun; Zhang, Lingzhi et al. (2016) Appoptosin interacts with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology. J Cell Sci 129:994-1002
Hu, Jin; Lin, Ting; Gao, Yuehong et al. (2015) The resveratrol trimer miyabenol C inhibits β-secretase activity and β-amyloid generation. PLoS One 10:e0115973
Zhao, Yingjun; Tseng, I-Chu; Heyser, Charles J et al. (2015) Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron 87:963-75
Jiang, Shangtong; Li, Yanfang; Zhang, Xian et al. (2014) Trafficking regulation of proteins in Alzheimer's disease. Mol Neurodegener 9:6
Wang, Xin; Huang, Timothy; Bu, Guojun et al. (2014) Dysregulation of protein trafficking in neurodegeneration. Mol Neurodegener 9:31

Showing the most recent 10 out of 55 publications