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      • HARVEST
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      P38(MAPK) negatively regulates monoamine oxidase-A activity as well as its sensitivity to Ca2+

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      Date
      2007
      Author
      Cao, Xia
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
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      Abstract
      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. 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, ƒÒ-amyloid (AƒÒ). 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.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Psychiatry
      Program
      Psychiatry
      Supervisor
      Mousseau, Darrell D.; Li, Xin-Min
      Committee
      Nazarali, Adil J.; Kalynchuk, Lisa E.; Baker, Glen; Yu, Peter H.
      Copyright Date
      2007
      URI
      http://hdl.handle.net/10388/etd-01032008-121637
      Subject
      Phosphorylation
      p38 MAP Kinase
      Mitochondria
      Calcium
      Mutagenesis
      Apoptosis
      Hydrogen Peroxide
      Activity
      Monoamine Oxidase
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      • Graduate Theses and Dissertations
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