Neuronal apoptosis and axon pruning are a normal part of vertebrate neurodevelopment;however, abnormal occurrences of these processes are the basis for many neuropathologies. One key regulator of neuronal death and degeneration is the p75 neurotrophin receptor. P75 is a multifunctional signaling protein, activating pathways that promote neuronal survival as well as apoptosis, axonal degeneration and the inhibition of axon growth. It has an essential role in regulating apoptosis of many neural populations during mammalian development. In addition, p75 signaling contributes to cell death following a wide variety of neural insults and has been suggested to play a role in the neuronal loss and degeneration seen in a number of neuropathologies. The overall objective of this proposal is to elucidate the molecular mechanisms by which p75 mediates neurodegeneration. Unfortunately, how the receptor transduces its signals and how they are differentially regulated to determine the ultimate cellular response is not well understood. We recently demonstrated that activation of p75 by BDNF in sympathetic neurons results in the stimulation of c-Jun N- terminal kinase (JNK) and this causes receptor proteolysis, first by the metalloprotease TACE followed by 3- secretase. The cleavage of p75 releases its intracellular domain (ICD) along with NRIF, a DNA binding protein, thereby facilitating NRIF translocation to the nucleus, which leads to apoptosis. Both receptor proteolysis and NRIF nuclear translocation are required for p75-mediated apoptosis in neurons. Interestingly, p75 and NRIF are detected not only in the neuronal cell body, but also in axons. Furthermore, addition of BDNF exclusively to distal axons in sympathetic neurons triggered cell death back at the soma, indicating that p75 can activate a retrograde apoptotic signal. However, if the neurons were simultaneously given NGF, then local BDNF treatment resulted in axon degeneration, but not apoptosis. We propose to determine the nature of this retrograde death signal and the mechanisms by which it is generated. Specifically, we hypothesize that p75's apoptotic signal involves activation of JNK, which stimulates endocytosis and cleavage of the receptor, resulting in a retrograde death signal involving the transcription factor NRIF. Furthermore, we propose that preventing retrograde signaling results in local axon degeneration. We will address these hypotheses by the following specific aims: (1) Determine whether NRIF is retrogradely trafficked in response to p75 activation by apoptotic ligands. (2) Determine whether p75 internalization and cleavage are necessary for retrograde apoptotic signaling. (3) Determine the role of JNK in retrograde signaling. (4) Determine whether axonal degeneration occurs when the retrograde apoptotic signal is blocked. The results from these studies will elucidate some of the differential mechanisms underlying neuronal death and axonal degeneration, both of which are involved in many neuropathologies.
The overall objective of this proposal is to elucidate the molecular mechanisms by which the p75 neurotrophin receptor mediates neuronal degeneration. This receptor regulates normal neuronal cell death and axonal pruning during the development of the mammalian retina, spinal cord, sensory and sympathetic neurons, and contributes to cell death following a wide variety of neural insults, such as injury to the spinal cord, hippocampus, and retina;it has also been suggested to play a role in the neuronal loss seen in a number of neuropathologies, such as Alzheimer's disease and stroke. Thus, understanding p75's signaling mechanisms has important implications for elucidating the etiology of many neurodegenerative conditions, as well as the fundamental regulation of normal neurodevelopment.
|Mobley, Bret C; Kwon, Minjae; Kraemer, Bradley R et al. (2015) Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis. PLoS One 10:e0133897|
|Kraemer, B R; Yoon, S O; Carter, B D (2014) The biological functions and signaling mechanisms of the p75 neurotrophin receptor. Handb Exp Pharmacol 220:121-64|
|Forsyth, Peter A; Krishna, Niveditha; Lawn, Samuel et al. (2014) p75 neurotrophin receptor cleavage by Î±- and Î³-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells. J Biol Chem 289:8067-85|
|Kraemer, Bradley R; Snow, John P; Vollbrecht, Peter et al. (2014) A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress. J Biol Chem 289:21205-16|
|Escudero, Claudia A; Lazo, Oscal M; Galleguillos, Carolina et al. (2014) The p75 neurotrophin receptor evades the endolysosomal route in neuronal cells, favouring multivesicular bodies specialised for exosomal release. J Cell Sci 127:1966-79|
|Wei, Chunyao; Thatcher, Elizabeth J; Olena, Abigail F et al. (2013) miR-153 regulates SNAP-25, synaptic transmission, and neuronal development. PLoS One 8:e57080|
|Schlebach, Jonathan P; Peng, Dungeng; Kroncke, Brett M et al. (2013) Reversible folding of human peripheral myelin protein 22, a tetraspan membrane protein. Biochemistry 52:3229-41|
|Perdigoto, Ana Luisa; Chaudhry, Nagarathnamma; Barnes, Gregory N et al. (2011) A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons. Mol Cell Neurosci 46:235-44|
|Astuti, Dewi; Ricketts, Christopher J; Chowdhury, Rasheduzzaman et al. (2011) Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility. Endocr Relat Cancer 18:73-83|
|Kenchappa, Rajappa S; Tep, Chhavy; Korade, Zeljka et al. (2010) p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17. J Biol Chem 285:20358-68|
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