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Determining The Molecular Mechanisms Of Huntington’S Disease Through Multi-Scale Modeling, Kiersten Ruff
Determining The Molecular Mechanisms Of Huntington’S Disease Through Multi-Scale Modeling, Kiersten Ruff
Arts & Sciences Electronic Theses and Dissertations
Huntington’s disease (HD) is associated with a mutational CAG repeat expansion within exon 1 of the huntingtin (Htt) gene. Post-transcriptional processing leads to the generation of N-terminal Htt protein fragments (Htt-NTFs), including those that encompass exon 1 (Httex1). Within Httex1, the CAG-repeat encoded polyglutamine (polyQ) tract is flanked N-terminally by a 17-residue amphipathic stretch (N17) and C-terminally by a 50-residue proline rich (PR) domain. Htt-NTFs, including Httex1, are among the smallest fragments that recapitulate HD pathology in mouse models. However, the direct link between Htt-NTFs with polyQ expansions and neurodegeneration that leads to HD remains unresolved. Despite being a monogenic …
Factors That Contribute To De Novo Protein Misfolding And Prion Formation In Saccharomyces Cerevisiae, Kathryn Morgan Keefer
Factors That Contribute To De Novo Protein Misfolding And Prion Formation In Saccharomyces Cerevisiae, Kathryn Morgan Keefer
Arts & Sciences Electronic Theses and Dissertations
Protein misfolding is a common phenomenon that can have severe consequences on cellular and organismal health. Despite this, the causes of protein misfolding remain poorly understood. Prions are a class of proteins that, when misfolded, can convert other molecules into a heritable, non-native conformation. The yeast Saccharomyces cerevisiae naturally harbors several diverse prion-forming proteins; thus, it is an ideal model with which to investigate the factors that influence misfolding and aggregation.This thesis utilizes the yeast prions [PSI+] and [RNQ+] to investigate two distinct steps of the protein misfolding pathway: interactions with chaperones and their cofactors, and heterologous templating by other …