CASPR facilitates clearance of degenerating axons by Schwann cells and macrophages after peripheral nerve injury

Abstract

In the peripheral nervous system (PNS) debris of injured axons is efficiently removed by Schwann cells (SCs) and macrophages (Mphs) - a process which is vital for nerve regeneration. Molecular so-called "eat-me" signals, mediating axon-SC/axon-Mph crosstalk and debris clearance after injury are just at the beginning of being identified. Herein, we describe the axonal node protein contactin-associated protein (CASPR) as a potential novel signal for axonal debris removal in peripheral nerve injury. In healthy nerves, CASPR is restricted to Ranviers nodes interacting with glia-derived partner proteins to assure saltatory action potential propagation. In injured murine and human nerves, we describe upregulation and re-localization of CASPR protein along the axons. Enhanced CASPR presence after injury appears to involve local axonal translation rather than transcriptional regulation. Of note, CASPR overexpression in murine central and peripheral neurons in vitro has a growth inhibitory effect. More importantly, axonal debris deriving from injured nerves - and hence having increased CASPR content - are phagocytosed more efficiently than debris of healthy nerves. Interfering with CASPR by function-blocking antibodies strongly reduces axonal debris uptake. This finding demonstrates a functional relevance of CASPR as a potential "eat me" signal in this process.