A proNGF and NGF binding protein, α2Macroglobulin, differentially regulates p75 and TrkA receptors and is relevant to neurodegeneration ex vivo and in vivo.

BARCELONA PF; SARAGOVI HU

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2015

erve growth factor (NGF) is generated from a precursor proNGF that is proteolytically procesed. NGF preferentially binds a trophic tyrosine kinase receptor TrkA, while proNGF binds a receptor p75NTR that can have neurotoxic activity. Previously, we and others showed that a soluble protein α2macroglobulin (α2M) is neurotoxic. Toxicity is due in part because α2M binds to NGF, and inhibits 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 α2M neurotoxicity. First, unexpectedly the [α2M?NGF] complexes do bind TrkA receptors, but do not induce TrkA dimerization or activation, resulting in deficient trophic support. Second, α2M makes stable complexes with proNGF, conveying resistant to proteolysis that results in more proNGF and less NGF. Third, [α2M?proNGF] complexes bind p75NTR, and are more potent agonists than free proNGF, inducing TNFα pr