A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

Nerve growth factor (NGF) is generated from a precursor, proNGF, that is proteolytically processed. NGF preferentially binds a trophic tyrosine kinase receptor, TrkA, while proNGF binds a neurotrophin receptor (NTR), p75(NTR), that can have neurotoxic activity. Previously, we along with others showed that the soluble protein alpha(2)-macroglobulin (alpha M-2) is neurotoxic. Toxicity is due in part to alpha M-2 binding to NGF and inhibiting trophic activity, presumably by preventing NGF binding to TrkA. However, the mechanisms remained unclear. Here, we show ex vivo and in vivo three mechanisms for alpha M-2 neurotoxicity. First, unexpectedly the alpha M-2-NGF complexes do bind TrkA receptors but do not induce TrkA dimerization or activation, resulting in deficient trophic support. Second, alpha M-2 makes stable complexes with proNGF, conveying resistance to proteolysis that results in more proNGF and less NGF. Third, alpha M-2-proNGF complexes bind p75(NTR) and are more potent agonists than free proNGF, inducing tumor necrosis factor alpha (TNF-alpha) production. Hence, alpha M-2 regulates proNGF/p75(NTR) positively and mature NGF/TrkA negatively, causing neuronal death ex vivo. These three mechanisms are operative in vivo, and alpha M-2 causes neurodegeneration in a p75(NTR)- and proNGF-dependent manner. alpha M-2 could be exploited as a therapeutic target, or as a modifier of neurotrophin signals.