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Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice
Classic homocystinuria is an inborn error of metabolism caused mainly by missense mutations leading to misfolded and/or unstable human cystathionine β-synthase (CBS) protein, causing the accumulation of excess total homocysteine (tHcy) in tissues. Previously, it has been shown that certain missense...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10270616/ https://www.ncbi.nlm.nih.gov/pubmed/37319242 http://dx.doi.org/10.1371/journal.pone.0286550 |
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author | Gupta, Sapna Lee, Hyung-Ok Wang, Liqun Kruger, Warren D. |
author_facet | Gupta, Sapna Lee, Hyung-Ok Wang, Liqun Kruger, Warren D. |
author_sort | Gupta, Sapna |
collection | PubMed |
description | Classic homocystinuria is an inborn error of metabolism caused mainly by missense mutations leading to misfolded and/or unstable human cystathionine β-synthase (CBS) protein, causing the accumulation of excess total homocysteine (tHcy) in tissues. Previously, it has been shown that certain missense containing human CBS proteins can be functionally rescued in mouse models of CBS deficiency by treatment with proteasome inhibitors. The rescue by proteasome inhibitors is thought to work both by inhibiting the degradation of misfolded CBS protein and by inducing the levels of heat-shock chaperone proteins in the liver. Here we examine the effectiveness of two FDA approved protease inhibitors, carfilzomib and bortezomib, on various transgenic mouse models of human CBS deficiency. Our results show that although both drugs are effective in inducing the liver chaperone proteins Hsp70 and Hsp27, and are effective in inhibiting proteasome function, bortezomib was somewhat more robust in restoring the mutant CBS function. Moreover, there was no significant correlation between proteasome inhibition and CBS activity, suggesting that some of bortezomib’s effects are via other mechanisms. We also test the use of low-doses of bortezomib and carfilzomib on various mouse models for extended periods of time and find that while low-doses are less toxic, they are also less effective at restoring CBS function. Overall, these results show that while restoration of mutant CBS function is possible with proteasome inhibitors, the exact mechanism is complicated and it will likely be too toxic for long-term patient treatment. |
format | Online Article Text |
id | pubmed-10270616 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-102706162023-06-16 Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice Gupta, Sapna Lee, Hyung-Ok Wang, Liqun Kruger, Warren D. PLoS One Research Article Classic homocystinuria is an inborn error of metabolism caused mainly by missense mutations leading to misfolded and/or unstable human cystathionine β-synthase (CBS) protein, causing the accumulation of excess total homocysteine (tHcy) in tissues. Previously, it has been shown that certain missense containing human CBS proteins can be functionally rescued in mouse models of CBS deficiency by treatment with proteasome inhibitors. The rescue by proteasome inhibitors is thought to work both by inhibiting the degradation of misfolded CBS protein and by inducing the levels of heat-shock chaperone proteins in the liver. Here we examine the effectiveness of two FDA approved protease inhibitors, carfilzomib and bortezomib, on various transgenic mouse models of human CBS deficiency. Our results show that although both drugs are effective in inducing the liver chaperone proteins Hsp70 and Hsp27, and are effective in inhibiting proteasome function, bortezomib was somewhat more robust in restoring the mutant CBS function. Moreover, there was no significant correlation between proteasome inhibition and CBS activity, suggesting that some of bortezomib’s effects are via other mechanisms. We also test the use of low-doses of bortezomib and carfilzomib on various mouse models for extended periods of time and find that while low-doses are less toxic, they are also less effective at restoring CBS function. Overall, these results show that while restoration of mutant CBS function is possible with proteasome inhibitors, the exact mechanism is complicated and it will likely be too toxic for long-term patient treatment. Public Library of Science 2023-06-15 /pmc/articles/PMC10270616/ /pubmed/37319242 http://dx.doi.org/10.1371/journal.pone.0286550 Text en © 2023 Gupta et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Gupta, Sapna Lee, Hyung-Ok Wang, Liqun Kruger, Warren D. Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice |
title | Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice |
title_full | Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice |
title_fullStr | Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice |
title_full_unstemmed | Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice |
title_short | Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice |
title_sort | examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10270616/ https://www.ncbi.nlm.nih.gov/pubmed/37319242 http://dx.doi.org/10.1371/journal.pone.0286550 |
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