Investigation of the synergistic role of PLK2 and alpha-synuclein in the regulation of neuronal homeostasis and functions

PLK2 和 α-突触核蛋白在神经元稳态和功能调节中的协同作用研究

• 批准号: RGPIN-2016-05860
• 负责人: Oueslati, Abid
• 金额: $ 1.82万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=680832
• 关键词: Investigation; synergistic; role; PLK2; alpha

Recent Progress: Alpha-synuclein (-syn) is a small soluble protein localized at presynaptic terminals in the central nervous system. Although this protein is abundantly expressed in the brain (1% of total cytosolic protein), its exact physiological functions remain unknown. In the past decade, there has been an increasing interest for the role of phosphorylation in the regulation of -syn normal function in vivo. In this context, our recent work identified Polo-like kinases (Plks) as the main kinases responsible for -syn phosphorylation in vitro and in vivo. Moreover, we reported that Plk2, a member of Plk family, regulates -syn selective clearance via the autophagy degradation pathway. However, the molecular mechanisms underlying Plk2-mediated -syn clearance and the exact synergistic physiological role of these two proteins remain unknown. ***Objective: The specific aims of the proposed research program are 1) to decipher the molecular mechanisms underlying -syn/Plk2 interaction and 2) to investigate the role of this pathway in the regulation of neuronal functions, with a focus in the control of the synaptic homeostasis.***Methodology: This research program is based on a multidisciplinary approach combining histological and biochemical analysis, cell-based assays using mammalian cells and primary neuronal culture, as well as in vivo animal models.***Impact: The 5-year deliverables of the proposed research program are 1) to identify new physiological functions of -syn and its natural kinase Plk2 and to shed light onto new molecular mechanisms underlying synaptic plasticity and homeostasis and 2) to train graduate students in molecular and cellular biology by developing a particular expertise in in vivo approaches.**

α -突触核蛋白（-syn）是一种位于中枢神经系统突触前末端的小可溶性蛋白。尽管这种蛋白在大脑中大量表达（占总胞质蛋白的1%），但其确切的生理功能尚不清楚。在过去的十年中，人们对磷酸化在体内调节-syn正常功能中的作用越来越感兴趣。在这种背景下，我们最近的工作确定了polo样激酶（Plks）是体外和体内负责-syn磷酸化的主要激酶。此外，我们报道了Plk家族成员Plk2通过自噬降解途径调节-syn选择性清除。然而，plk2介导的-syn清除的分子机制以及这两种蛋白的确切协同生理作用尚不清楚。***目的：研究-syn/Plk2相互作用的分子机制；研究-syn/Plk2相互作用在神经元功能调控中的作用，重点研究突触稳态的调控。***方法：本研究项目基于多学科方法，结合组织学和生化分析，利用哺乳动物细胞和原代神经元培养的基于细胞的分析，以及体内动物模型。***影响：该研究计划的5年成果包括：1)确定-syn及其天然激酶Plk2的新生理功能，揭示突触可塑性和体内平衡的新分子机制；2)通过发展体内方法的特定专业知识，培养分子和细胞生物学的研究生