Monoamine oxidase (MAO) is a mitochondrial deaminating enzyme that exists as two isoforms, MAO-A and -B. The MAO-mediated reaction generates hydrogen peroxide (H2O2) as a normal by-product. Dysregulation of MAO has been implicated in a variety of neuropsychiatric and neurodegenerative disorders, as well as in the aging process. Endogenous regulators of MAO-A function include calcium (Ca2+) and the p38 mitogen-activated protein kinase (MAPK). Although the effect of p38(MAPK) is thought to rely on induction of mao-A gene expression, post-translational modification of the MAO-A protein is also possible. <p>Using standard biochemical approaches in combination with pharmacological interventions and recombinant DNA strategies, specific aspartic acid residues (within putative Ca2+-binding motifs) were demonstrated to contribute to MAO-A activity. Furthermore, MAO-A activity and its sensitivity to Ca2+ was negatively regulated by the p38(MAPK), which is usually activated during cell stress. The effect of p38(MAPK) on MAO-A function relies specifically on Serine209 in MAO-A, which resides in a p38(MAPK) consensus motif. The serine phosphorylation status of MAO-A determines its capacity for generating peroxy radicals and its toxicity in established cell lines (e.g. C6, N2a, HEK293A, HT-22) and in primary cortical neurons. p38(MAPK)-regulated MAO-A activity is also linked to neurotoxicity associated with the Alzheimer disease-related peptide, Ò-amyloid (AÒ). These data suggest a unique neuroprotective role for p38(MAPK) centered on a negative feedback regulation of the Ca2+-sensitive, H2O2-generating enzyme MAO-A.
| Identifer | oai:union.ndltd.org:USASK/oai:usask.ca:etd-01032008-121637 |
| Date | 04 January 2008 |
| Creators | Cao, Xia |
| Contributors | Nazarali, Adil J., Mousseau, Darrell D., Li, Xin-Min, Kalynchuk, Lisa E., Baker, Glen, Yu, Peter H. |
| Publisher | University of Saskatchewan |
| Source Sets | University of Saskatchewan Library |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-01032008-121637/ |
| 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 University of Saskatchewan 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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