Interaction of proneurotrophin-induced apoptotic signaling and mature neurotrophin-induced survival signaling in rat brain

SONG, WENYU; VOLOSIN, MARTA; CRAGNOLINI, ANDREA BEATRIZ; HEMPSTEAD, BARBARA L; FRIEDMAN, WILMA J

Congreso; Society for Neuroscience Meeting; 2009

Proneurotrophins and mature neurotrophins can activate distinct signaling pathways with opposing cellular consequences: proneurotrophins induce apoptotic signaling via p75NTR, while mature neurotrophins activate survival signaling through Trk receptors. In the CNS, basal forebrain (BF) neurons express both p75NTR and Trk receptors. We demonstrated previously that proneurotrophins induce loss of BF neurons through p75NTR, even in the presence of activated Trk receptors. Moreover, proNGF inhibited BDNF-induced Akt phosphorylation, suggesting that proNGF induced apoptotic signaling and simultaneously blocked survival signaling activated by BDNF. Phosphorylation of Akt can prevent proNGF-induced apoptosis, suggesting that regulation of Akt activation may be a critical point of interaction between survival and death signaling. We have also shown that PTEN (phosphatase and tensin homologue deleted on chromosome ten), a dual-specificity phosphatase that can act as an antagonist to the PI3K/Akt pathway, can be upregulated by proNGF via p75NTR to inhibit survival signaling. Furthermore, in the presence of mature neurotrophins, this death signaling is inhibited when PTEN activity is inhibited both in vitro and in vivo, suggesting that PTEN is a crucial factor mediating the balance between p75NTR-induced apoptotic signaling and Trk-mediated survival signaling.