Neurotrophins are a family of factors that influence a multiplicity of functions in the central nervous system that range from supporting neuronal survival to eliciting apoptosis, regulating synaptic function, and influencing axonal growth. These distinct functions are mediated by the interactions of the factors with two distinct receptors, a member of the Trk family of receptor tyrosine kinases and the p75 neurotrophin receptor (NTR). It has recently been shown that neurotrophin precursors, proneurotrophins, selectively bind and activate p75NTR, effectively eliciting apoptosis, while the mature (cleaved) neurotrophins preferentially activate Trk signaling, which supports neuronal survival. Many neurons express Trk receptors and p75NTR, especially after injury when p75NTR is upregulated. In the proposed studies we will investigate how the signaling pathways activated by these different receptors interact to determine how neurons respond when exposed concomitantly to mature and proneurotrophins, as occurs after injury. Our previous studies have shown that p75NTR initiates apoptotic signaling while supressing Trk-mediated survival signaling. Our proposed studies will explore these mechanisms further. One key determinant of whether Trk or p75NTR is activated depends on which form of the ligand, mature or proneurotrophins, are available to bind the different receptors. Since proneurotrophins can be secreted and cleaved extracellularly, we will investigate the regulation of proneurotrophin cleavage, particlarly after seizures when we have detected increases in proneurotrophins in the CNS, and induction of p75NTR-mediated apoptosis. The p75NTR can function as a co-receptor with several other receptors to mediate different functions. The high-affinity binding of proneurotrophins to is due to the interaction with a co-receptor, sortilin, and our preliminary studies have shown that both receptors are required for proneurotrophins to elicit apoptosis. The signals that determine the association of p75NTR with its different co-receptors are unknown, and we will investigate this question in the proposed studies. In sum, these studies will provide greater insight into the multifunctional effects of neurotrophins in the brain, particularly under inflammatory conditions that occur after injury or in disease.

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In these studies we will investigate the mechanisms by which neurotrophins regulate neuronal survival or death in the brain. We have previously determined that after seizures there is an increase in the p75 neurotrophin receptor that mediates neuronal cell death. Our studies will elucidate the mechanisms by which these key factors regulate neuronal death when the p75 receptor is induced, which occurs after different types of brain injury, as well as in neurodegenerative disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Mamounas, Laura
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Rutgers University
Schools of Arts and Sciences
United States
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Choi, S; Friedman, W J (2014) Interleukin-1? enhances neuronal vulnerability to proNGF-mediated apoptosis by increasing surface expression of p75(NTR) and sortillin. Neuroscience 257:11-9
Le, Audrey P; Friedman, Wilma J (2012) Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. J Neurosci 32:703-12
Cragnolini, Andrea B; Volosin, Marta; Huang, Yangyang et al. (2012) Nerve growth factor induces cell cycle arrest of astrocytes. Dev Neurobiol 72:766-76
Song, Wenyu; Volosin, Marta; Cragnolini, Andrea B et al. (2010) ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J Neurosci 30:15608-15
Friedman, Wilma J (2010) Proneurotrophins, seizures, and neuronal apoptosis. Neuroscientist 16:244-52
Choi, Soyoung; Friedman, Wilma J (2009) Inflammatory cytokines IL-1? and TNF-? regulate p75NTR expression in CNS neurons and astrocytes by distinct cell-type-specific signalling mechanisms. ASN Neuro 1:
Cragnolini, Andrea B; Huang, Yangyang; Gokina, Pradeepa et al. (2009) Nerve growth factor attenuates proliferation of astrocytes via the p75 neurotrophin receptor. Glia 57:1386-92
Volosin, Marta; Trotter, Christy; Cragnolini, Andrea et al. (2008) Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures. J Neurosci 28:9870-9
Cragnolini, Andrea B; Friedman, Wilma J (2008) The function of p75NTR in glia. Trends Neurosci 31:99-104