Significance
Cyclin-dependent kinase 5 (Cdk5) hyperactivity is an important driver of pathology in neurodegeneration. Normally, Cdk5 is regulated by association with its co-activators p35 or p39. Cdk5 hyperactivity is caused by calpain-mediated cleavage of p35 into the truncated activator p25, which binds to Cdk5 and leads to prolonged activation and altered substrate specificity. Preventing p25 production by destroying the calpain cleavage site in p35 abolishes neurodegenerative phenotypes in mouse models, but this genetic approach does not present a viable therapeutic strategy. Here, we report a 12-amino acid long Cdk5-derived peptide that interferes with the Cdk5/p25 complex and ameliorates neurodegenerative phenotypes in cell and mouse models of Cdk5 hyperactivity. This small peptide is a promising candidate for a biotherapeutic against neurodegenerative diseases.
Abstract
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.
