Myelin‐associated glycoprotein alters the neuronal secretome and stimulates the release of TGFβ and proteins that affect neural plasticity

Abstract

Myelin‐associated glycoprotein (MAG) and Nogo inhibit neurite outgrowth by binding to receptors such as NgR1, PirB and LRP1, and they have also been shown to induce phosphorylation of Smad2, a key intermediate in the transforming growth factor β (TGFβ) signalling pathway. In this study, we determined that MAG and Nogo do not transactivate the TGFβ receptor through their canonical receptors or discoidin domain receptor 1, which we identified as a novel receptor for MAG and Nogo. Instead, MAG and Nogo promoted Smad2 phosphorylation by stimulating secretion of TGFβ. Proteomic analysis of the neuronal secretome revealed that MAG also regulated the secretion of proteins that affect central nervous system plasticity—inducing the secretion of S100A6, septin‐7 and neurofascin 186, while inhibiting the secretion of frataxin, MAP6, syntenin‐1 and GAP‐43. This represents a novel function for MAG that has broad implications for the treatment for spinal cord injury.

S100A6 Protein—Expression and Function in Norm and Pathology

“…The presence of S100A6 has been reported for example in the culture medium of decidual cells [ 142 ] or cerebellar granule neurons treated with myelin-associated glycoprotein [ 143 ]. It has been also detected in extracellular matrix of Wharton’s jelly [ 144 ], amnion fluid [ 145 ], pancreatic juice [ 107 , 146 ], urine [ 147 , 148 ] and tears [ 149 ]. Recent results have shown that S100A6 is present in nasal lavage fluid [ 150 ], and its level is elevated in the nasal swabs of COVID-19 patients [ 151 ].…”

“…However, it was proposed to regulate secretory processes since, when added to the medium, it stimulated the secretion of lactogen II by trophoblast cells [ 142 ] and the release of insulin from pancreatic cells [ 41 , 152 ] and of histamine from mast cells [ 153 ]. In the case of mesenchymal stem cells of the Wharton’s jelly extracellular S100A6 caused an increase in cell adhesion and, contrary to the intracellular protein, inhibited their proliferation [ 144 ].…”