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AR Thesis Revision May 2016.pdf (8.58 MB)

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The role MAPK1 plays in Drp1 activation leading to mitochondrial dysfunction in Huntington's disease.

Roe, Anne Jessica T
http://rave.ohiolink.edu/etdc/view?acc_num=case1459431850

Abstract Details

2016, Master of Sciences, Case Western Reserve University, Physiology and Biophysics.
Huntington’s disease (HD) is an incurable neurodegenerative disease with autosomal dominant inheritance caused by expanded CAG repeats in the huntingtin gene that confers a toxic gain-of-function on mutant huntingtin (mtHtt) protein. Mitochondrial dysfunction is a major cytopathology in HD. However, the molecular mechanisms by which mtHtt affect mitochondrial function remains elusive. This project explores the role MAPK1 plays in the over-activation of Drp1, the mitochondrial fission protein, which leads to the mitochondrial dysfunction and neurodegeneration seen in HD. Hdh striatal cells, treated with U0126, a potent inhibitor of MEK1/2, showed a decrease in mitochondrial fragmentation, and restored mitochondrial function. We show MAPK1 binding to and phosphorylating Drp1 at Ser616 in HD, as well as U0126 treatment abolishing this phosphorylation. A phosphorylation-deficient mutant of Drp1, S616A, also corrected the mitochondrial fragmentation associated with HD. This study suggests that MAPK1 activation of the mitochondrial fission machinery leads to the aberrant mitochondrial dysfunction and neurodegeneration seen in HD; and that inhibition of Drp1-mediated excessive mitochondrial fission can be used as a treatment for HD.
Xin Qi (Advisor)
William Schilling (Committee Chair)
George Dubyak (Committee Member)
Joseph LaManna (Committee Member)
Charles Hoppel (Committee Member)
80 p.
Neurology; Physiology
MAPK1; Drp1; Huntingtons disease; mitochondrial dysfunction

Recommended Citations

Citations

  • Roe, A. J. T. (2016). The role MAPK1 plays in Drp1 activation leading to mitochondrial dysfunction in Huntington's disease. [Master's thesis, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1459431850

    APA Style (7th edition)

  • Roe, Anne Jessica. The role MAPK1 plays in Drp1 activation leading to mitochondrial dysfunction in Huntington's disease. 2016. Case Western Reserve University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1459431850.

    MLA Style (8th edition)

  • Roe, Anne Jessica. "The role MAPK1 plays in Drp1 activation leading to mitochondrial dysfunction in Huntington's disease." Master's thesis, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459431850

    Chicago Manual of Style (17th edition)

case1459431850
289
© 2016, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.