Publication Date

2019-05-08

Availability

Embargoed

Embargo Period

2021-05-07

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience (Medicine)

Date of Defense

2019-01-22

First Committee Member

Antonio Barrientos

Second Committee Member

Carlos Moraes

Third Committee Member

Miguel Perez-Pinzon

Fourth Committee Member

Abigail Hackam

Abstract

Neurodegenerative proteopathies result from neurotoxicity induced by the misfolding and oligomerization of disease-specific proteins. These proteopathies include polyglutamine (polyQ) disorders such as Huntington’s disease (HD), a-synucleinopathies such as Parkinson’s disease, and tauopathies such as Alzheimer’s disease. Previous work from our lab and others has shown robust suppression of proteoxicity through the overexpression of NMA1/NMNAT and other NAD+ biosynthetic enzymes in yeast, flies, and mice. However, the precise mechanism involved in this suppression remains controversial. To investigate this question further, we used a yeast model of Huntington’s as well as in vitro assays to evaluate how NMA1 and other yeast NAD+ biosynthetic enzymes confer protection in the presence of disease-causing proteins. In particular, we were interested in elucidating whether the catalytic function of NAD+ biosynthetic enzymes is required for their protective capacity. Through a variety of assays both in vitro and in a yeast model of Huntington’s disease, we observed that mutations to the catalytic core of NAD+ biosynthetic enzymes do not disrupt protective function, and that NAD+ biosynthetic enzymes do act independently as chaperone proteins. These results provide exciting insights into the complexity of protein functions, as well as new insights that may help lead to new treatments for protein misfolding disorders.

Keywords

NMNAT; huntingtin; proteotoxicity; NAD salvage pathway; polyglutamine; PolyQ

Available for download on Friday, May 07, 2021

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