Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Beverly L. Davidson

Abstract

Huntington’s disease (HD) is an autosomal dominant disease known for its severe neurologic phenotype. However, the causative protein in HD, mutant huntingtin (mHTT), is widely expressed across tissue types and may have profound consequences for peripheral organs. Notably, heart disease is the second leading cause of death in HD patients, but if or how cardiac mHTT expression causes pathology is still unknown. Here, I characterize the cardiac phenotype in two HD mouse models and show that dysregulated mTORC1 activity is a key underlying mechanism. I show that normal heart growth is limited in HD mouse models, with mass regulated independent of systemic changes. Additionally, cardiac mTORC1 activity is decreased in HD mice starting at a presymptomatic time point in a manner that requires cardiac mHTT expression. The impaired activity results from decreased PI3K/Akt/mTOR signaling at early time points and Rheb mislocalization at later disease stages. As a result of mTORC1 dysregulation, HD mice have increased mortality, inability to hypertrophy, and increased pathologic changes in response to stress. Notably, this phenotype is reversed in HD mice with exogenously activated mTORC1. Thus, I propose that mHTT expression in HD hearts dysregulates mTORC1 and leads to increased mortality with heart disease.

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