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

伴侣蛋白是每一个细胞中的基本因子。通过控制蛋白质的正确折叠和组装，它们确保了蛋白质在不同水平上的正确结构和功能。至于其他隔室，外周神经系统(PNS)的活动受到适当的伴侣活性的影响，因为蛋白质在细胞体、轴突和突触末梢水平上的正确折叠和功能是必不可少的。神经肌肉接头(NMJ)是神经元、肌肉和终末雪旺细胞共同协作建立和维持三叉神经节与组织之间的联系的三方突触。在三叉神经节，雪旺细胞可分为四大类：包裹神经轴突并传递信号的髓鞘细胞，包裹轴突并使它们保持分离的非髓鞘细胞，与神经元细胞体相关的卫星细胞，以及在NMJ对突触生长、功能和维持至关重要的突触周围细胞。肽基-脯氨酰异构酶A(PPIA)又称亲环素A，是一种广泛表达的伴侣蛋白，主要定位于中枢神经系统，在神经元中表达最高。在中枢神经系统中，PPIA与神经元生长有关，它的缺失会导致聚集蛋白的增加。文献证据表明，PPIA可能参与轴突运输和树枝形成。PPIA可由不同类型的细胞在细胞外释放，通过与其受体EMMPRIN(细胞外基质金属蛋白酶诱导物)结合，可作为促炎分子、趋化因子或基质金属蛋白酶(MMPs)释放的诱导剂发挥作用。MMPs参与轴突生长和NMJ的形成和维持。除了在神经元中的高表达外，还没有关于PPIA在三叉神经节和外周突触水平上的表达、释放和功能的研究。本研究计划旨在首次研究PPIA在三叉神经核中的参与，特别是在外周轴突和NMJ的水平上。我们将研究PPIA在运动神经元轴突延长、引导和运输中的作用，以及PPIA在NMJ形成和维持中参与神经元、肌肉和雪旺细胞之间的信号转导的细胞内和细胞外参与。我们希望描述PPIA在轴突生理学中的重要作用，从货物的运输到突触在肌肉中的定居，并破译它在构成NMJ的不同细胞群体中的作用，以及它们之间的沟通。通过拟议的研究计划，我们的目标是产生有助于理解和表征PNS的踏脚石结果，在NMJ水平上细胞群体的相互作用，以及像PPIA这样的多任务伴侣蛋白在上述间隔中从未被描述的参与。

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.