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Differential Effects of Molecular Chaperones on Various Types of Protein Aggregates
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Differential Effects of Molecular Chaperones on Various Types of Protein Aggregates
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Dissertation
Differential Effects of Molecular Chaperones on Various Types of Protein Aggregates
2020
Overview
Proteins have the intrinsic ability to convert from their native functional state intoinsoluble fibrous protein aggregates known as amyloids. The assembly of differentmisfolded proteins into amyloid fibrils is a key feature in a wide range of human amyloiddiseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease,Amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease to name a few. My thesiswork has focused on understanding how molecular chaperones and protein degradationmachineries operate in a continuous system of checks and balances to maintainproteostasis in eukaryotic cells. Firstly, I have characterized evolutionarily conserved,essential eukaryotic members of the AAA+ superfamily, RuvbL1, and RuvbL2 (yeasthomologs Rvb1 and Rvb2), as novel mammalian disaggregases capable of reversing heatshock damage as well as key chaperones in modulating the formation of the aggresomequality control compartment in yeast. Secondly, I have shown that depletion of Rvb1, Rvb2or its adaptor protein, Tah1, has differential effects on the aggregation patterns of differentamyloidogenic proteins such as Amyloid β and MAPT (associated with Alzheimer'sdisease in humans) and Sup35 (an endogenous yeast protein capable of forming the selfperpetuating amyloid state, termed [PSI+] prion). Lastly, I have characterized a novelprocess by which the ubiquitin-proteasome machinery exerts its effects on proteinscontaining an amyloid core. Our work has shown that the E3 ligase Rsp5, capable ofubiquitinating the chaperones Hsp104 and Hsp70-Ssb, modulates the effects of thesechaperones on the propagation and formation of self-perpetuating amyloid aggregates(prions) in yeast. Overall, this work provides new information on how molecularchaperones and protein degradation pathways cope with protein aggregation.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798263345303
