Unravelling the functions of Peptidyl-Prolyl Isomerase A in axonal transport and neuromuscular junction development and maintenance.

揭示肽基脯氨酰异构酶 A 在轴突运输和神经肌肉接头发育和维护中的功能。

• 批准号: RGPIN-2021-03394
• 负责人: Pozzi, Silvia
• 金额: $ 2.19万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763644
• 关键词: Unravelling; functions; Peptidyl; Prolyl; Isomerase

Chaperone proteins are essential factors in every cells. By governing the proper folding and assembly of proteins they ensure the correct structure and function of proteins at different levels. As for others compartments, the activity of peripheral nervous system (PNS) is influenced by a proper chaperones activity since the correct folding and function of proteins are necessary in the cell body, along the axon and at the terminal synaptic level. The neuromuscular junction (NMJ) is as tripartite synapse where neurons, muscles and terminal Schwann cells cooperate to create and maintain the connection between the PNS and tissues. In the PNS, Schwann cells can be divided into four main groups: the myelinating cells that wrap the axons in nerves and allows signal to be transmitted, the non-myelinating cells that wrap axons and keep them separated, the satellite cells that associate with neuronal cells body, and the perisynaptic cells that are essential at the NMJ for synaptic growth, function and maintenance. Peptidyl-Prolyl Isomerase A (PPIA), also known as cyclophilin A, is a ubiquitously expressed chaperone mainly localized in the central nervous system (CNS) with highest expression in neurons. In the CNS, PPIA has been implicated in neuronal growth and its absence induces an increase of aggregated proteins. Evidence from literature points out the possible involvement of PPIA in axonal transport and arborisation. PPIA can be released in the extracellular space by different cell types and, by binding to its receptor EMMPRIN (extracellular matrix metalloproteinase inducer), it can work as a proinflammatory molecule, as chemoattractant factor or as an inducer of matrix metalloproteinases (MMPs) release. MMPs are implicated in axonal growth and NMJ formation and maintenance. Except for its high expression in neurons, no studies have addressed the expression, release, and function of PPIA in the PNS and at the level of peripheral synapses like the NMJ. The present research program aims to investigate for the first time the involvement of PPIA in the PNS and, in particular, at the level of peripheral axons and NMJs. We will investigate the function of PPIA in axonal elongation, guidance and transport in motor neurons and the intracellular and extracellular involvement of PPIA in the signaling among neurons, muscles and Schwann cells in NMJ formation and maintenance. We expect to describe an essential role for PPIA in axonal physiology, from transport of cargos to synapse settlement in muscles, and to decipher its role both inside the different cellular populations that constitute the NMJ, and in their communication. With the proposed research program, we aim to produce steppingstone results that will contribute in the understanding and characterization of the PNS, the interplay of cellular populations at the NMJ level and a never described involvement of a multitasking chaperone protein like PPIA in the aforementioned compartments.

伴侣蛋白是每个细胞的必需因子。通过控制蛋白质的正确折叠和组装，它们确保蛋白质在不同水平上的正确结构和功能。对于其他区室，周围神经系统（PNS）的活性受到适当的分子伴侣活性的影响，因为蛋白质的正确折叠和功能在细胞体中、沿着轴突和在末端突触水平是必需的。 神经肌肉接头（NMJ）是神经元、肌肉和终末雪旺细胞共同建立和维持PNS与组织连接的三联突触。 在PNS中，许旺细胞可以分为四个主要组：包裹神经中的轴突并允许信号传递的髓鞘形成细胞，包裹轴突并保持它们分离的非髓鞘形成细胞，与神经元细胞体相关联的卫星细胞，以及在NMJ中对于突触生长，功能和维持至关重要的突触周细胞。 肽基脯氨酰异构酶A（PPIA），也称为亲环素A，是一种广泛表达的伴侣蛋白，主要定位于中枢神经系统（CNS），在神经元中表达最高。在CNS中，PPIA与神经元生长有关，其缺乏诱导聚集蛋白的增加。文献证据指出PPIA可能参与轴突运输和树枝化。PPIA可以通过不同类型的细胞在细胞外空间释放，并且通过与其受体EMMPRIN（细胞外基质金属蛋白酶诱导剂）结合，它可以作为促炎分子、作为化学引诱因子或作为基质金属蛋白酶（MMP）释放的诱导剂起作用。MMPs参与轴突生长和NMJ形成和维持。 除了它在神经元中的高表达，没有研究涉及PPIA在PNS和外周突触如NMJ水平的表达，释放和功能。本研究计划旨在首次调查PPIA在PNS中的参与，特别是在外周轴突和NMJ水平。我们将研究PPIA在运动神经元轴突延伸、引导和运输中的功能，以及PPIA在神经元、肌肉和雪旺细胞之间的信号传导中的细胞内和细胞外参与，以形成和维持NMJ。 我们期望描述PPIA在轴突生理学中的重要作用，从货物的运输到肌肉中的突触定居，并破译其在构成NMJ的不同细胞群体内的作用，以及它们的通信。通过拟议的研究计划，我们的目标是产生垫脚石结果，这将有助于理解和表征PNS，NMJ水平上细胞群体的相互作用以及从未描述过的多任务伴侣蛋白如PPIA在上述隔室中的参与。