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

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

Included in

Biophysics Commons

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