A cyclin-dependent kinase 5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes
| Autor: | Jay Penney, Debasis Patnaik, Oleg Kritskiy, Stephen J. Haggarty, Ping-Chieh Pao, Jinsoo Seo, M. Catarina Silva, Li-Huei Tsai, Scarlett J. Barker, Michael Bula, Audrey Lee, L Ashley Watson |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Activator (genetics) Chemistry Kinase DNA damage Cyclin-dependent kinase 5 Neurodegeneration Peptide medicine.disease 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine nervous system Gliosis medicine medicine.symptom Kinase activity 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/2020.05.12.090472 |
| Popis: | Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This effect is mediated by pathological cleavage of the Cdk5 activator p35 to produce the truncated product p25, exhibiting increased stability and altered substrate specificity. The benefit of blocking p25 production has been demonstrated in various rodent and human neurodegenerative models. However, important Cdk5/p35 functions in the developing and adult brain have made it challenging to selectively target the detrimental effects of Cdk5/p25 while sparing the physiological functions of Cdk5/p35. Here, we report a 12-amino acid-long peptide fragment derived from Cdk5 (the Cdk5 inhibitory (Cdk5i) peptide) that shows a high binding affinity toward the Cdk5/p25 complex and can efficiently and selectively inhibit Cdk5/p25 kinase activity. Using cellular assays, mouse neurodegeneration models and human cerebral organoids generated from patient-derived iPSCs, we demonstrate beneficial effects of the Cdk5i peptide on various pathological phenotypes including gliosis, DNA damage, and Tau hyperphosphorylation. |
| Databáze: | OpenAIRE |
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