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In partial fulfillment of the requirements for the degree of
Doctor of Philosophy in Biology
In the
School of Biological Sciences
Rakhee Chhabria Ganti
Will defend her dissertation
DIFFERENTIAL EFFECTS OF MOLECULAR CHAPERONES ON VARIOUS TYPES OF PROTEIN AGGREGATES
Friday, October 9th, 2020
11:00 AM
https://bluejeans.com/373440017/
Meeting ID: 373 440 017
Thesis Advisor:
Yury Chernoff, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Committee Members:
Kirill Lobachev, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Matt Torres, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Amit Reddi, Ph.D.
Chemistry and Biochemistry
Georgia Institute of Technology
Lary Walker, Ph.D.
Department of Neurology
Emory University
DIFFERENTIAL EFFECTS OF MOLECULAR CHAPERONES ON VARIOUS TYPES OF PROTEIN AGGREGATES
Proteins have the intrinsic ability to convert from their native functional state into insoluble fibrous protein aggregates known as amyloids. The assembly of different misfolded proteins into amyloid fibrils is a key feature in a wide range of proteopathies, including Alzheimer's disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease to name a few. My work has focused on understanding how molecular chaperones and protein degradation machineries operate in a continuous system of checks and balances to maintain proteostasis in eukaryotic cells. Firstly, I have characterized evolutionarily conserved, essential eukaryotic members of the AAA+ superfamily, RuvbL1 and RuvbL2 (yeast homologs Rvb1 and Rvb2), as novel mammalian disaggregases capable of reversing heat shock damage as well as key chaperones in modulating the formation of the aggresome quality control compartment in yeast. Secondly, I have shown that depletion of Rvb1, Rvb2 or its adaptor protein, Tah1, has differential effects on the aggregation patterns of different amylogenic proteins such as Abeta and Tau (associated with Alzheimer’s disease in humans) and Sup35 (an endogenous yeast protein capable of forming the self-perpetuating amyloid state, termed [PSI+] prion). Lastly, I have characterized a novel process by which the ubiquitin-proteasome machinery exerts its effects on proteins containing an amyloid core. Our work has shown that the E3 ligase Rsp5, capable of ubiquitinating the chaperones Hsp104 and Hsp70-Ssb, modulates the effects of these chaperones on the propagation and formation self-perpetuating amyloid aggregates (prions) in yeast. Overall, our work provides new information on how molecular chaperones and protein degradation pathways cope with protein aggregation. These data can be applied to better understanding events causing human amyloid diseases.
