L-DOPA Induced Dyskinesia (LID) is the motor complication involving an overproduction of movement that arises from L-DOPA treatment of Parkinson's disease (PD). Despite the high incidence of the development of LID, the etiology of this side effect and variability in its speed of onset is still poorly understood. Previous work in the lab discovered that subjects with PD who had developed LID had less striatal mitochondrial DNA (mtDNA), relative to non-dyskinetic PD and healthy subjects. The focus of this research was thus to identify mechanisms by which reduced mtDNA might affect the function of the striatal neurons typically affected by LID. Through treating primary murine striatal cultures with low doses of ethidium bromide (EtBr) to selectively inhibit mtDNA replication and transcription, it was determined that mtDNA reduction reduces mitochondrial respiration in neurons and astrocytes, but selectively increases glycolytic activity in astrocytes. Further, decreased mtDNA selectively reduces the expression of mitochondrial creatine kinase in neurons, which is accompanied by a reduction in phosphocreatine quantity. Creatine and phosphocreatine act as crucial energy distributing molecules to facilitate the transfer of mitochondrially-synthesized ATP-phosphates to other sites of high energy demand in the cytosol. Consequently, reduced phosphocreatine production, arising from reduced mtDNA, may impair efficient energy transfer in the striatum. This may contribute to the development of maladaptive signaling pathways associated with LID.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-02092018-155542 |
| Date | 13 February 2018 |
| Creators | Warren, Emily Booth |
| Contributors | Joshua P. Fessel, M.D., Ph.D., Christine Konradi, Ph.D., Eugenia Gurevich, Ph.D., Aaron B. Bowman, Ph.D., Qi Zhang, Ph.D. |
| 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-02092018-155542/ |
| 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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