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

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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.