Retromer deficiency and Alzheimer's disease pathology

逆转录酶缺乏与阿尔茨海默病病理学

• 批准号: 9605932
• 负责人: WEN-CHENG XIONG
• 金额: $ 32.8万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9605932
• 关键词: Retromer; deficiency; Alzheimer; disease; pathology

DESCRIPTION (provided by applicant): VPS35 is a major component of retromer that is essential for selective endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is implicated in the pathogenesis of Alzheimer's disease (AD) as well as Parkinson's disease (PD), because mutations in Vps35 and SorLA (a cargo of retromer) genes have been identified in the late-onset PD and AD patients, respectively. Thus, it is of considerable interest to investigate how VPS35/retromer deficiency contributes to neurodegeneration. Three hypotheses will be tested in this proposal. The first hypothesis is that VPS35/retromer expression in pyramidal neurons is critical to prevent AD-relevant neuropathology. The second hypothesis is that VPS35/retromer deficient neurons are impaired in BACE1 retrograde trafficking, thus increasing BACE1 activity and promoting dendritic and axonal degeneration. The third hypothesis is that VPS35/retromer deficient microglial cells are hypersensitive to TNF� family cytokines, releasing excessive proinflammatory cytokines and promoting brain inflammation and neurodegeneration. Both hypotheses are supported by our publications and recent preliminary studies. We hope that the proposed studies will not only establish novel cellular functions of VPS35/retromer in preventing hyper-activation of BACE1 and microglia, but also shed new lights into pathogenesis of neurodegenerative disorders, such as AD and PD. We also hope that this research may point to new therapeutic strategies for the treatment of these disorders.

描述（由申请人提供）：VPS35是逆转录酶的主要成分，对于膜蛋白的选择性内体到高尔基体修复至关重要。VPS35/逆转录酶的功能障碍与阿尔茨海默病（AD）以及帕金森病的发病机制有关。 (PD)，因为在晚发性 PD 和 AD 患者中分别发现了 Vps35 和 SorLA（retromer）基因突变。因此，研究 VPS35/retromer 缺陷如何导致神经变性非常有意义。第一个假设是锥体神经元中的 VPS35/retromer 表达对于预防 AD 相关的神经病理学至关重要。 VPS35/retromer 缺陷的神经元在 BACE1 逆行运输中受损，从而增加 BACE1 活性并促进树突和轴突变性。 VPS35/retromer 缺陷的小胶质细胞对 TNFα 家族细胞因子高度敏感，释放过量的促炎细胞因子并促进脑部炎症和神经变性。我们希望所提出的研究不仅能建立新的细胞功能。 VPS35/retromer 可以预防 BACE1 和小胶质细胞的过度激活，同时也为 AD 和 PD 等神经退行性疾病的发病机制提供新的线索。治疗这些疾病的治疗策略。

项目成果

Vps35 haploinsufficiency results in degenerative-like deficit in mouse retinal ganglion neurons and impairment of optic nerve injury-induced gliosis.

• DOI: 10.1186/1756-6606-7-10
• 发表时间: 2014-02-11
• 期刊: Molecular brain
• 影响因子: 3.6
• 作者: Liu W;Tang FL;Erion J;Xiao H;Ye J;Xiong WC
• 通讯作者: Xiong WC

Myosin X Interaction with KIF13B, a Crucial Pathway for Netrin-1-Induced Axonal Development.

• DOI: 10.1523/jneurosci.0929-20.2020
• 发表时间: 2020-11-25
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Yu HL;Peng Y;Zhao Y;Lan YS;Wang B;Zhao L;Sun D;Pan JX;Dong ZQ;Mei L;Ding YQ;Zhu XJ;Xiong WC
• 通讯作者: Xiong WC

Lactate Metabolism, Signaling, and Function in Brain Development, Synaptic Plasticity, Angiogenesis, and Neurodegenerative Diseases.

• DOI: 10.3390/ijms241713398
• 发表时间: 2023-08-29
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death.

• DOI: 10.3390/ijms22168394
• 发表时间: 2021-08-04
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Zhao Y;Tang F;Lee D;Xiong WC
• 通讯作者: Xiong WC

YAP Is a Critical Inducer of SOCS3, Preventing Reactive Astrogliosis.

YAP 是 SOCS3 的关键诱导剂，可预防反应性星形胶质细胞增生。

• DOI: 10.1093/cercor/bhv292
• 发表时间: 2016-05
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Huang Z;Wang Y;Hu G;Zhou J;Mei L;Xiong WC
• 通讯作者: Xiong WC