Master of Science (MS)
Date of Defense
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
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.
NMNAT; huntingtin; proteotoxicity; NAD salvage pathway; polyglutamine; PolyQ
Ruetenik, Andrea, "The Role of NAD Salvage Pathway Proteins in Proteotoxicity Suppression" (2019). Open Access Theses. 769.
Available for download on Friday, May 07, 2021