TitleThe role of proneurotrophins in apoptotic signaling in rat brain neurons
NameSong, Wenyu (author), Friedman, Wilma (chair), Jonakait, G (internal member), Kim, Haesun (internal member), Dreyfus, Cheryl (outside member), Rutgers University, Graduate School - Newark,
DescriptionProneurotrophins and mature neurotrophins can activate distinct signaling pathways and have opposing effects on cells: proneurotrophins induce apoptotic signaling via p75NTR while mature neurotrophins activate survival signaling by binding to Trk receptors. In the CNS, basal forebrain (BF) neurons express both p75NTR and Trk receptors. The work in this thesis demonstrates that proneurotrophins can induce loss of BF neurons through p75NTR, even in the presence of activated Trk receptors. Moreover, proNGF inhibits the phosphorylation of Akt induced by BDNF, suggesting that proNGF induces apoptotic signaling and simultaneously blocks survival signaling activated by BDNF. Phosphorylation of Akt can prevent proNGF-induced apoptosis, suggesting that regulation of Akt phosphorylation may be a critical point of interaction between survival and death signaling.
PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a dual-specificity phosphatase that can act as an antagonist to the PI3 kinase/Akt pathway. ProNGF induces an increase in PTEN in BF neurons, even in the presence of BDNF, suggesting that proNGF might block survival signaling through PTEN. In the presence of BDNF, proNGF was unable to induce apoptosis when PTEN activity was inhibited both in vitro and in vivo. Also, the PTEN inhibitor blocked proNGF-induced inhibition of Akt phosphorylation by BDNF, suggesting that PTEN is a crucial factor mediating the balance between p75-induced apoptotic signaling and Trk-mediated survival signaling.
Taken together, the interaction of proneurotrophin-p75NTR and mature neurotrophin-Trk systems is partially determined by the balance of PTEN and Akt which eventually causes the cell to die or survive.
NoteIncludes bibliographical references (p. 97-119)
Noteby Wenyu Song
CollectionGraduate School - Newark Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.