Cell-Based Mechanism Mediating Prion Loss and Stability
The prion protein underlies several previously inexplicable phenomena, including transmissible neurodegenerative disease in mammals and the non-Mendelian inheritance of unique traits in fungi. These proteins can adopt multiple stable conformations, and each of these forms can self-replicate by assem...
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ndltd-arizona.edu-oai-arizona.openrepository.com-10150-6263112018-01-15T03:00:28Z Cell-Based Mechanism Mediating Prion Loss and Stability Pei, Fen Pei, Fen Serio, Tricia R. Serio, Tricia R. Schroeder, Joyce A. Bolger, Tim A. Ghosh, Indraneel The prion protein underlies several previously inexplicable phenomena, including transmissible neurodegenerative disease in mammals and the non-Mendelian inheritance of unique traits in fungi. These proteins can adopt multiple stable conformations, and each of these forms can self-replicate by assembling into ordered aggregates, which template the conversion of the newly synthesized protein into the prion form as these monomers join the aggregates. These complexes must then be fragmented to generate additional templates and to promote the spread of the aggregates both within and between individuals. Despite its efficient and autocatalytic pathways of protein misfolding, changes in prion self-replication cycles can inhibit prion persistence and thus the transmission of prion-associated phenotypes. In our studies, we first explored this inhibition process using a yeast prion [PSI+], the prion form of a translation termination factor Sup35, and a dominant-negative mutant of this protein. Prion variants with distinct conformations were differentially sensitive to prion inhibition, despite the fact that each of the variants were impacted by the mutant in the same way - a reduction in kinetic stability and an increased sensitivity to fragmentation. The threshold for clearance of the existing aggregates was determined by both the self-replication efficiencies of the variants and also the dosage of the mutant, indicating that changing dosing regimes might be effective for treating prion variants. In addition to dominant-negative mutant inhibition, prion persistence can also be inhibited by heat shock. Our studies indicate that this inhibition requires the activity of the deacetylase Sir2, which promotes asymmetric retention of misfolded proteins after cellular stress. Intriguingly, Sir2 mediates its effects through a mating-type specific gene YJL133C-A, which localizes to the mitochondrial membrane. Together, our studies indicate that prion persistence and clearance arise from a complex interplay between prion protein conformation and sequence and the cellular environment in which they reside. 2017 text Electronic Dissertation http://hdl.handle.net/10150/626311 http://arizona.openrepository.com/arizona/handle/10150/626311 en_US Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. The University of Arizona. |
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The prion protein underlies several previously inexplicable phenomena, including transmissible neurodegenerative disease in mammals and the non-Mendelian inheritance of unique traits in fungi. These proteins can adopt multiple stable conformations, and each of these forms can self-replicate by assembling into ordered aggregates, which template the conversion of the newly synthesized protein into the prion form as these monomers join the aggregates. These complexes must then be fragmented to generate additional templates and to promote the spread of the aggregates both within and between individuals. Despite its efficient and autocatalytic pathways of protein misfolding, changes in prion self-replication cycles can inhibit prion persistence and thus the transmission of prion-associated phenotypes. In our studies, we first explored this inhibition process using a yeast prion [PSI+], the prion form of a translation termination factor Sup35, and a dominant-negative mutant of this protein. Prion variants with distinct conformations were differentially sensitive to prion inhibition, despite the fact that each of the variants were impacted by the mutant in the same way - a reduction in kinetic stability and an increased sensitivity to fragmentation. The threshold for clearance of the existing aggregates was determined by both the self-replication efficiencies of the variants and also the dosage of the mutant, indicating that changing dosing regimes might be effective for treating prion variants. In addition to dominant-negative mutant inhibition, prion persistence can also be inhibited by heat shock. Our studies indicate that this inhibition requires the activity of the deacetylase Sir2, which promotes asymmetric retention of misfolded proteins after cellular stress. Intriguingly, Sir2 mediates its effects through a mating-type specific gene YJL133C-A, which localizes to the mitochondrial membrane. Together, our studies indicate that prion persistence and clearance arise from a complex interplay between prion protein conformation and sequence and the cellular environment in which they reside. |
author2 |
Serio, Tricia R. |
author_facet |
Serio, Tricia R. Pei, Fen Pei, Fen |
author |
Pei, Fen Pei, Fen |
spellingShingle |
Pei, Fen Pei, Fen Cell-Based Mechanism Mediating Prion Loss and Stability |
author_sort |
Pei, Fen |
title |
Cell-Based Mechanism Mediating Prion Loss and Stability |
title_short |
Cell-Based Mechanism Mediating Prion Loss and Stability |
title_full |
Cell-Based Mechanism Mediating Prion Loss and Stability |
title_fullStr |
Cell-Based Mechanism Mediating Prion Loss and Stability |
title_full_unstemmed |
Cell-Based Mechanism Mediating Prion Loss and Stability |
title_sort |
cell-based mechanism mediating prion loss and stability |
publisher |
The University of Arizona. |
publishDate |
2017 |
url |
http://hdl.handle.net/10150/626311 http://arizona.openrepository.com/arizona/handle/10150/626311 |
work_keys_str_mv |
AT peifen cellbasedmechanismmediatingprionlossandstability AT peifen cellbasedmechanismmediatingprionlossandstability |
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1718610910551998464 |