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The molecular mechanisms of free 3-nitrotyrosine neurotoxicity

Ma, Thong Chi
http://rave.ohiolink.edu/etdc/view?acc_num=osu1189707727

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Pharmacy.
The increased production of reactive nitrogen species (RNS), such as peroxynitrite, has been linked to neuron death in many neurodegenerative diseases. RNS can modify tyrosine to form 3-nitrotyrosine (3NT) and levels of 3NT are elevated in these disorders. While a useful marker for RNS, 3NT may also be harmful to neurons. Free 3NT is directly toxic to dopaminergic neurons and we have investigated the mechanisms by which free 3NT causes neuron death in this dissertation. We have found that free 3NT may be toxic to neurons by three mechanisms. First, free 3NT caused the selective apoptosis of dopaminergic neurons and sensitized non-dopaminergic neurons to toxicity from dopamine-generated oxidants in cell culture. This was associated with mitochondrial impairment through complex I inhibition and increased oxidant production. Free 3NT may be directly toxic to dopaminergic neurons by sensitizing them to endogenously-generated dopamine. Second, free 3NT enhanced excitotoxicity and caused calcium deregulation following brief exposures to glutamate in forebrain cultures. Our data suggest that free 3NT impairs calcium removal from neurons by a mechanism independent of mitochondrial inhibition. Instead, elevated sodium levels following glutamate exposure may underlie the impairment of calcium efflux and calcium buffering. Finally, free 3NT was transported into neurons and astrocytes in our cultures and was reversibly incorporated into alpha-tubulin, a cytoskeletal protein. While this did not affect the gross morphology of our cells, subtle changes in cytoskeletal organization or disruption of protein-cytoskeleton interactions may occur and could adversely affect neuronal function. Collectively, our data suggest that free 3NT production and accumulation is detrimental to neuron health. While free 3NT is not directly toxic to all types of neurons, it clearly sensitizes them to additional stressors. These stressors (i.e. dopamine autooxidation) may confer specific toxicity of free 3NT to certain types of neurons. As 3NT levels are increased in neurodegenerative disease, free 3NT accumulation could contribute to neuron loss in these disorders.
Kari Hoyt (Advisor)
193 p.
3-nitrotyrosine; neurodegeneration; excitotoxicity; reactive nitrogen species; dopamine

Recommended Citations

Citations

  • Ma, T. C. (2007). The molecular mechanisms of free 3-nitrotyrosine neurotoxicity [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1189707727

    APA Style (7th edition)

  • Ma, Thong. The molecular mechanisms of free 3-nitrotyrosine neurotoxicity. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1189707727.

    MLA Style (8th edition)

  • Ma, Thong. "The molecular mechanisms of free 3-nitrotyrosine neurotoxicity." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1189707727

    Chicago Manual of Style (17th edition)

osu1189707727
481
© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.