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Targeting mitochondria as a potential therapeutic strategy in neurodegenerative disease

Hu, Di
http://rave.ohiolink.edu/etdc/view?acc_num=case1559999737544078

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Mitochondrion is a dynamic organelle whose ATP production depends heavily on the precise coordination of thousands of proteins. Mitochondrial quality control strategy plays an essential role in maintaining mitochondrial function and integrity. Impairment of mitochondrial function associated with neurodegenerative disease is widely evidenced. In Parkinson’s disease (PD), though α-synuclein-induced mitochondrial dysfunction has been broadly demonstrated, the mechanisms by which α-synuclein impacts mitochondria is poorly understood. We identified mitochondrial matrix protease ClpP whose expression and peptidase activity was downregulated by α-synuclein in PD. Factors that compensate for the loss of ClpP reduced the production of mitochondrial ROS and the accumulation of unfolded protein, and enhanced neuronal viability suggesting the translational potential of ClpP in the treatment with PD. Mitochondrial dysfunction induced by mutant huntingtin protein (mtHtt) is a distinct feature and has been suggested as a determinant of neuronal loss in Huntington’s disease (HD). Inspired by our previous findings that blocking the translocation of mitochondrial fission regulator Drp1 could sufficiently ameliorate HD-associated phenotypes, we targeted mitochondrial function for drug development. We identified CHIR99201 as a mitochondrial enhancer via high throughput screening (HTS). Treatment with CHIR99201 efficiently rescued mitochondrial membrane potential and respiration, and reduced HD-related neuropathology and motor deficits. We proposed a model by which CHIR99201 reduced mitochondrial fragmentation through the inhibition of calpain/CDK5/p25 by upregulating the expression of calpastatin. Overall, our comprehensive analyses focusing on both mechanistic understanding and treatment validation reveal targeting mitochondria as a potential translational approach in neurodegenerative diseases.
Sudha Chakrapani (Committee Chair)
Corey Smith (Committee Member)
George Dubyak (Committee Member)
Andrew Pieper (Committee Member)
Xin Qi (Advisor)
181 p.
Neurobiology

Recommended Citations

Citations

  • Hu, D. (2019). Targeting mitochondria as a potential therapeutic strategy in neurodegenerative disease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1559999737544078

    APA Style (7th edition)

  • Hu, Di. Targeting mitochondria as a potential therapeutic strategy in neurodegenerative disease. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1559999737544078.

    MLA Style (8th edition)

  • Hu, Di. "Targeting mitochondria as a potential therapeutic strategy in neurodegenerative disease." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1559999737544078

    Chicago Manual of Style (17th edition)

case1559999737544078
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© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.