Author ORCID Identifier
Semester
Fall
Date of Graduation
2023
Document Type
Dissertation
Degree Type
PhD
College
School of Pharmacy
Department
Pharmaceutical Sciences
Committee Chair
Visvanathan Ramamurthy
Committee Member
Marina Galvez Peralta
Committee Member
Werner Geldenhuys
Committee Member
David M. Smith
Committee Member
Peter Stoilov
Abstract
Cells rely on heat shock proteins (HSP) to facilitate and regulate the folding of the substrate proteins into their native state, and degradation if misfolding cannot be prevented. HSP90, a member of the HSP family, is a potential target for treatment of cancer and neurodegenerative diseases. Unfortunately, several clinical trials for cancer treatment have been discontinued due to cell toxicity accompanying HSP90 inhibition. HSP90 has four distinct but structurally similar paralogs. HSP90 inhibitors target all the paralogs despite increasing proof of functional differences among the paralogs. Understanding the in vivo function of HSP90 and the role played by each paralog in the cell is a prerequisite in discovering potent HSP90-based drugs.
In the past few years, we focused on assessing the role of cytosolic HSP90α and β paralog in the cell using a mouse model. HSP90α and β proteins are highly homologous (93% similar), yet the need for these distinct isoforms and their clients is unknown. Interestingly, HSP90 inhibitors in clinical trials for cancer treatment led to night blindness in humans. Intriguingly, inhibition of HSP90 in mice shows a reduction in phosphodiesterase 6 (PDE6) levels, the effector enzyme in phototransduction signaling. At the same time, Aryl-hydrocarbon-interacting protein-like1(AIPL1), a cochaperone of HSP90, regulates the stability and assembly of PDE6 subunits. In this study, we have analyzed the relationship between HSP90 and PDE6 regulation. Our study indicated that HSP90α is needed in the maintenance of visual function. Unexpectedly, our finding demonstrated that HSP90α is needed to maintain the stability of PDE6 subunits and their cochaperone AIPL1. Interestingly, HSP90β was upregulated in the absence of HSP90α in the retina, likely to maintain the HSP90 pool in the cytosol and regulate functions shared among these paralogs.
Lastly, targeting HSP90 for cancer or neurodegenerative treatment is not feasible due to non-specific side effects caused by using HSP90 inhibitors at high doses or prolonged use. We investigated the potential of targeting the activator of HSP90 ATPase 1 (AHA1), a cochaperone that accelerates the folding cycle of HSP90. Previous studies indicated that AHA1 inhibition could be used to treat neurodegenerative diseases such as Alzheimer’s, Huntington, and Cystic fibrosis. We investigated whether AHA1 is needed in normal cellular function. Our studies show that AHA1 deficiency does not affect overall health of the animals. In fact, AHA1 deletion in a Retinitis pigmentosa model significantly improved vision and delayed photoreceptor death.
In conclusion, we have shown that HSP90α plays a role in visual function, indicating the root cause of ocular toxicities in patients using HSP90 inhibition-based drugs. Our findings added new proof to the existing genetic studies showing that HSP90 isoforms have their unique role and substrate in the cell. In addition, our study indicated that HSP90 inhibition is not an ideal drug target, but targeting other HSP90 system components, such as cochaperone AHA1 may be a viable option for treatment of cancer or neurodegenerative diseases.
Recommended Citation
Munezero, Daniella, "Heat Shock Protein 90 (HSP90) system in health and disease." (2023). Graduate Theses, Dissertations, and Problem Reports. 12287.
https://researchrepository.wvu.edu/etd/12287
Embargo Reason
Publication Pending
Included in
Amino Acids, Peptides, and Proteins Commons, Animal Experimentation and Research Commons, Biochemistry Commons, Biotechnology Commons, Disease Modeling Commons, Eye Diseases Commons, Genetics Commons, Medical Molecular Biology Commons, Molecular and Cellular Neuroscience Commons, Molecular Genetics Commons