Semester
Fall
Date of Graduation
2024
Document Type
Dissertation
Degree Type
PhD
College
School of Medicine
Department
Biochemistry
Committee Chair
Maxim Sokolov
Committee Member
Michelle Bridi
Committee Member
Visvanathan Ramamurthy
Committee Member
David Smith
Committee Member
Peter Stoilov
Abstract
Nearly all neurodegenerative diseases (NDs) and some eye diseases are characterized by the presence of misfolded and aggregated proteins. The ubiquitin proteasome system (UPS) is responsible for degrading the majority of proteins including misfolded and aggregated proteins. However, in NDs the performance of the UPS is impaired, and this impairment partially comes from these protein aggregates inhibiting the proteasome. This inhibition leads to an accumulation of protein aggregates, more proteasomal inhibition, and fewer chaperones for newly synthesized proteins, triggering a collapse in proteostasis, which is thought to contribute to the pathogenesis of NDs. Consequently, stimulating proteasome function is being investigated as a therapeutic strategy to treat NDs and eye diseases. Here we evaluated an alternative approach, expression of the archaeal proteasome subunits, PAN and the 20S to stimulate protein degradation. Hypothetically, PANand the archaeal 20S could increase proteostasis and reduce disease-associated protein aggregates by facilitating protein refolding, reducing protein aggregation, or enhancing protein degradation. Although, there was concern that an exogenous unfoldase and protease would be detrimental to mammalian cells, we found that PAN and the archaeal 20S proteasome did not reduce photoreceptor function or viability. We also show that PAN increased photoreceptor survival and visual function in two mouse models with protein misfolding retinopathy. These results support that archaeal proteasomes may be an effective therapeutic approach to increase protein turnover in eye diseases and NDs with protein-misfolding etiology.
Recommended Citation
Brooks, Celine, "Evaluating the efficacy of the archaeal proteasome to alleviate protein-misfolding retinopathy" (2024). Graduate Theses, Dissertations, and Problem Reports. 12635.
https://researchrepository.wvu.edu/etd/12635
