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. 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 120(2023), 16 vom: 18. Apr., Seite e2217864120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pao, Ping-Chieh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.04.2023 Date Revised 16.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2217864120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM355479702 |
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| 100 | 1 | |a Pao, Ping-Chieh |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 14.04.2023 | ||
| 500 | |a Date Revised 16.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Alzheimer’s disease | |
| 650 | 4 | |a Cdk5 | |
| 650 | 4 | |a neurodegenerative disease | |
| 650 | 4 | |a tauopathy | |
| 650 | 7 | |a Cyclin-Dependent Kinase 5 |2 NLM | |
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| 700 | 1 | |a Seo, Jinsoo |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Audrey |e verfasserin |4 aut | |
| 700 | 1 | |a Kritskiy, Oleg |e verfasserin |4 aut | |
| 700 | 1 | |a Patnaik, Debasis |e verfasserin |4 aut | |
| 700 | 1 | |a Penney, Jay |e verfasserin |4 aut | |
| 700 | 1 | |a Raju, Ravikiran M |e verfasserin |4 aut | |
| 700 | 1 | |a Geigenmuller, Ute |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, M Catarina |e verfasserin |4 aut | |
| 700 | 1 | |a Lucente, Diane E |e verfasserin |4 aut | |
| 700 | 1 | |a Gusella, James F |e verfasserin |4 aut | |
| 700 | 1 | |a Dickerson, Bradford C |e verfasserin |4 aut | |
| 700 | 1 | |a Loon, Anjanet |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Margaret X |e verfasserin |4 aut | |
| 700 | 1 | |a Bula, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Melody |e verfasserin |4 aut | |
| 700 | 1 | |a Haggarty, Stephen J |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Li-Huei |e verfasserin |4 aut | |
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