DOI
10.17077/etd.wzigce9s
Document Type
Dissertation
Date of Degree
Spring 2015
Degree Name
PhD (Doctor of Philosophy)
Degree In
Molecular Physiology and Biophysics
First Advisor
Beverly L. Davidson
First Committee Member
Amy Lee
Second Committee Member
Charles Harata
Third Committee Member
Andrew Russo
Fourth Committee Member
Michael Anderson
Fifth Committee Member
Pedro Gonzalez-Alegre
Abstract
Huntington's Disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is selective vulnerability in a specific brain region known as the striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in striatal tissues from HD mouse models and patients, and show that further mTORC1 impairment in mouse models, achieved through the knockdown of Rhes, a striatum-enriched mTORC1 activator, exacerbates disease phenotypes. In contrast, exogenous addition of Rhes or the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, and elicits increased autophagy, and reverses impaired dopamine signaling. Furthermore, while HD has been considered primarily a neurological disease, organs with high metabolic demand, such as heart, are also severely affected. The mechanism by which mHTT disrupts cardiac function remains unknown. I provide evidence that mTORC1 is impaired in HD mouse model hearts, causing hyperactive FoxO1 signaling which may render HD hearts vulnerable to stress induced cardiomyopathy. In sum, my combined work indicates impaired mTORC1 signaling as a primary mechanism underlying the neurodegenerative and heart-related disease phenotypes in HD, and thus presents a rational therapeutic target.
Pages
117 pages
Bibliography
Includes bibliographical references (pages 105-117).
Copyright
Copyright © 2015 John Hung Lee
Recommended Citation
Lee, John Hung. "Altered mTOR signaling in Huntington's Disease." PhD (Doctor of Philosophy) thesis, University of Iowa, 2015.
https://doi.org/10.17077/etd.wzigce9s.