A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α 2 -Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

Abstract

ABSTRACT 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 α 2 -macroglobulin (α 2 M) is neurotoxic. Toxicity is due in part to α 2 M 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 α 2 M neurotoxicity. First, unexpectedly the α 2 M-NGF complexes do bind TrkA receptors but do not induce TrkA dimerization or activation, resulting in deficient trophic support. Second, α 2 M makes stable complexes with proNGF, conveying resistance to proteolysis that results in more proNGF and less NGF. Third, α 2 M-proNGF complexes bind p75 NTR and are more potent agonists than free proNGF, inducing tumor necrosis factor alpha (TNF-α) production. Hence, α 2 M regulates proNGF/p75 NTR positively and mature NGF/TrkA negatively, causing neuronal death ex vivo . These three mechanisms are operative in vivo , and α 2 M causes neurodegeneration in a p75 NTR - and proNGF-dependent manner. α 2 M could be exploited as a therapeutic target, or as a modifier of neurotrophin signals.