The p75 Neurotrophin Receptor (p75NTR) is a critical regulator of axon pruning and apoptosis during neurodevelopment. Because the receptor has also been associated with many injurious or pathological conditions involving oxidative stress, this dissertation project aimed to investigate a role for p75NTR in neurodegeneration induced by oxidative injury. Our work revealed that receptor is activated by 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product naturally generated during oxidative stress. Treatment of sympathetic neurons with HNE caused axonal degeneration and programmed cell death; however, neurons lacking p75NTR were significantly protected from these effects. HNE exposure was not associated with production of neurotrophins, and a ligand-blocking antibody failed to prevent HNE-induced apoptosis, thus suggesting that oxidative stress activates the receptor through a neurotrophin-independent mechanism. HNE exposure resulted in metalloprotease- and γ-secretase-dependent cleavage of p75NTR, and pharmacological inhibition of these proteolytic events protected neurons from HNE-induced apoptosis. Lastly, p75NTR-/- mice were resistant to oxidative injury caused by administration of 6-hydroxydopamine in vivo. Altogether, these findings indicate that in response to oxidative stress p75NTR is activated through a ligand-independent event which triggers cleavage of the receptor by a metalloprotease and γ-secretase, thereby leading to axonal degeneration and apoptosis.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08252014-160042 |
| Date | 28 August 2014 |
| Creators | Kraemer, Bradley Rhoads |
| Contributors | Christine L. Konradi, William H. Valentine, Aaron B. Bowman, Bruce D. Carter, Scott W. Hiebert |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08252014-160042/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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