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A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes

Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity...

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Autores principales: Pao, Ping-Chieh, Seo, Jinsoo, Lee, Audrey, Kritskiy, Oleg, Patnaik, Debasis, Penney, Jay, Raju, Ravikiran M., Geigenmuller, Ute, Silva, M. Catarina, Lucente, Diane E., Gusella, James F., Dickerson, Bradford C., Loon, Anjanet, Yu, Margaret X., Bula, Michael, Yu, Melody, Haggarty, Stephen J., Tsai, Li-Huei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120002/
https://www.ncbi.nlm.nih.gov/pubmed/37043533
http://dx.doi.org/10.1073/pnas.2217864120
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author Pao, Ping-Chieh
Seo, Jinsoo
Lee, Audrey
Kritskiy, Oleg
Patnaik, Debasis
Penney, Jay
Raju, Ravikiran M.
Geigenmuller, Ute
Silva, M. Catarina
Lucente, Diane E.
Gusella, James F.
Dickerson, Bradford C.
Loon, Anjanet
Yu, Margaret X.
Bula, Michael
Yu, Melody
Haggarty, Stephen J.
Tsai, Li-Huei
author_facet Pao, Ping-Chieh
Seo, Jinsoo
Lee, Audrey
Kritskiy, Oleg
Patnaik, Debasis
Penney, Jay
Raju, Ravikiran M.
Geigenmuller, Ute
Silva, M. Catarina
Lucente, Diane E.
Gusella, James F.
Dickerson, Bradford C.
Loon, Anjanet
Yu, Margaret X.
Bula, Michael
Yu, Melody
Haggarty, Stephen J.
Tsai, Li-Huei
author_sort Pao, Ping-Chieh
collection PubMed
description Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity. Elevated p25 levels have been reported in humans and rodents with neurodegeneration, and the benefit of genetically blocking p25 production has been demonstrated previously in rodent and human neurodegenerative models. Here, we report a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) that is considerably smaller than existing peptide inhibitors of Cdk5 (P5 and CIP) but shows high binding affinity toward the Cdk5/p25 complex, disrupts the interaction of Cdk5 with p25, and lowers Cdk5/p25 kinase activity. When tagged with a fluorophore (FITC) and the cell-penetrating transactivator of transcription (TAT) sequence, the Cdk5i-FT peptide exhibits cell- and brain-penetrant properties and confers protection against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models of neurodegeneration, highlighting Cdk5i’s therapeutic potential.
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spelling pubmed-101200022023-10-12 A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes Pao, Ping-Chieh Seo, Jinsoo Lee, Audrey Kritskiy, Oleg Patnaik, Debasis Penney, Jay Raju, Ravikiran M. Geigenmuller, Ute Silva, M. Catarina Lucente, Diane E. Gusella, James F. Dickerson, Bradford C. Loon, Anjanet Yu, Margaret X. Bula, Michael Yu, Melody Haggarty, Stephen J. Tsai, Li-Huei Proc Natl Acad Sci U S A Biological Sciences Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity. Elevated p25 levels have been reported in humans and rodents with neurodegeneration, and the benefit of genetically blocking p25 production has been demonstrated previously in rodent and human neurodegenerative models. Here, we report a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) that is considerably smaller than existing peptide inhibitors of Cdk5 (P5 and CIP) but shows high binding affinity toward the Cdk5/p25 complex, disrupts the interaction of Cdk5 with p25, and lowers Cdk5/p25 kinase activity. When tagged with a fluorophore (FITC) and the cell-penetrating transactivator of transcription (TAT) sequence, the Cdk5i-FT peptide exhibits cell- and brain-penetrant properties and confers protection against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models of neurodegeneration, highlighting Cdk5i’s therapeutic potential. National Academy of Sciences 2023-04-12 2023-04-18 /pmc/articles/PMC10120002/ /pubmed/37043533 http://dx.doi.org/10.1073/pnas.2217864120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Pao, Ping-Chieh
Seo, Jinsoo
Lee, Audrey
Kritskiy, Oleg
Patnaik, Debasis
Penney, Jay
Raju, Ravikiran M.
Geigenmuller, Ute
Silva, M. Catarina
Lucente, Diane E.
Gusella, James F.
Dickerson, Bradford C.
Loon, Anjanet
Yu, Margaret X.
Bula, Michael
Yu, Melody
Haggarty, Stephen J.
Tsai, Li-Huei
A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
title A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
title_full A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
title_fullStr A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
title_full_unstemmed A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
title_short A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
title_sort cdk5-derived peptide inhibits cdk5/p25 activity and improves neurodegenerative phenotypes
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120002/
https://www.ncbi.nlm.nih.gov/pubmed/37043533
http://dx.doi.org/10.1073/pnas.2217864120
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