A novel signaling mechanism of Progranulin

颗粒体蛋白前体的新型信号机制

• 批准号: 8533057
• 负责人: Fenghua Hu
• 金额: $ 22.49万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8533057
• 关键词: Accounting; Alzheimer' s Disease; Binding; Biological Assay; Bypass; Cell Line; Cell surface; Cells; Complex; Data; Dementia; Development; Endocytosis; Event; Frontotemporal Lobar Degenerations; Genes; Genetic Polymorphism; Glycoproteins; Goals; Integral Membrane Protein; Maps; Measures; Mediating; Modeling; Molecular; Motor Neurons; Mus; Mutation; Nerve Degeneration; Neurons; PGRN gene; Patients; Peptides; Pharmaceutical Preparations; Play; Progranulin; Proteolysis; Resistance; Risk Factors; Role; Signal Transduction; Site; Subfamily lentivirinae; Testing; Therapeutic; Ubiquitin; Work; early onset; genetic linkage; granulin; neuronal survival; novel; prevent; protein TDP-43; protein aggregate; receptor; small hairpin RNA; sortilin; trafficking

DESCRIPTION (provided by applicant): Mutations in Progranulin (PGRN), a gene encoding a secreted glycoprotein, are the major cause of Frontotemporal Lobar Degeneration with ubiquitin positive inclusions (FTLD-U). More recently, TMEM106B, a type II transmembrane protein of unknown function, was discovered as a risk factor of FTLD-U. But how PGRN and TMEM106B function together to prevent FTLD-U remains unclear. Our previous work has identified sortilin as a PGRN trafficking receptor. Our recent preliminary data further suggests that sortilin plays a role in mediating PGRN signaling. Lack of a signaling motif in sortilin intracellular region suggests the presence of a potential 'co-receptor". We found that TMEM106B physically interacts with sortilin and this interaction stimulates the cleavage of TMEM106B. Furthermore, TMEM106B is a substrate of regulated intramembrane proteolysis (RIP), which is known to play a critical role in neuronal signal transduction. Thus we propose that sortilin and TMEM106B form a receptor complex for PGRN and TMEM106B cleavage mediates PGRN signaling. To test this model, two specific aims are proposed. Aim1: To determine the role of sortilin/TMEM106B in PGRN signaling. We will first test the importance of sortilin and TMEM106B in PGRN signaling by measuring the neurotrophic effects of PGRN in neurons lacking sortilin or TMEM106B. Then we will determine whether PGRN signaling stimulates sortilin/TMEM106B interaction and TMEM106B cleavage. Aim2: To investigate the signaling mechanism of TMEM106B. We will first generate a cleavage resistant version of TMEM106B to determine whether TMEM106B cleavage is required for PGRN signaling. Then the cleavage product of TMEM106B will be expressed in NSC-34 cells to determine whether it has neurotrophic effects similar to PGRN treatment. We also plan to probe the downstream signaling mechanisms of TMEM106B cleavage product by examining its localization and identifying its binding partners. In summary, through these studies, we expect to establish a role of sortilin and TMEM106B in PGRN signaling and test a novel signaling mechanism involving TMEM106B cleavage. We expect our proposed studies will significantly advance our understanding on PGRN signaling mechanisms and will establish the first molecular characterization of TMEM106B and illustrate its role in neurodegeneration.

描述（申请人提供）：编码分泌的糖蛋白的基因（PGRN）中的突变（PGRN）是额颞Lobar变性伴有泛素阳性夹杂物（FTLD-U）的主要原因。最近，TMEM106B是一种功能未知的II型跨膜蛋白，被发现是FTLD-U的危险因素。但是，PGRN和TMEM106B如何共同起作用以防止FTLD-U，尚不清楚。我们以前的工作已将Tortilin确定为PGRN运输受体。我们最近的初步数据进一步表明，Tortilin在介导PGRN信号传导中起作用。 sortilin的细胞内区域缺乏信号传导基序表明存在潜在的“共受体”。我们发现TMEM106B与sortilin进行了物理相互作用，这种相互作用刺激了TMEM106B的分裂。此外，TMEM106B的temem106b是批判性内部prote prane prote a primate pranembrane Prote a a是批判性properrane a a rip a rip a rip a rip s的siptrate a rip s的基础，因此，我们提出，pgrn和TMEM106B的受体复合物和TMEM106B的裂解介导了PGRN信号。 PGRN在缺乏Tornilin或TMEM106B中的神经营养作用。用于PGRN信号。然后将在NSC-34细胞中表达TMEM106B的切割产物，以确定其是否具有类似于PGRN治疗的神经营养作用。我们还计划通过检查其本地化并识别其结合伙伴，探测TMEM106B切割产物的下游信号传导机制。总而言之，通过这些研究，我们希望在PGRN信号传导中建立Torsilin和TMEM106B的作用，并测试涉及TMEM106B裂解的新型信号传导机制。我们预计我们的拟议研究将显着提高我们对PGRN信号传导机制的理解，并将建立TMEM106B的第一个分子表征，并说明其在神经变性中的作用。