2. Academic Validation
  3. A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes

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

  • Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2217864120. doi: 10.1073/pnas.2217864120.
Ping-Chieh Pao 1 2,  Jinsoo Seo 1 2 3,  Audrey Lee 1 2,  Oleg Kritskiy 1 2,  Debasis Patnaik 4,  Jay Penney 1 2,  Ravikiran M Raju 1 2 5,  Ute Geigenmuller 1 2,  M Catarina Silva 4,  Diane E Lucente 6 7,  James F Gusella 6 8,  Bradford C Dickerson 7,  Anjanet Loon 1 2,  Margaret X Yu 1 2,  Michael Bula 1 2,  Melody Yu 1 2,  Stephen J Haggarty 4,  Li-Huei Tsai 1 2
Affiliations

Affiliations

  • 1 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 2 Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • 3 Department of Brain Sciences, Daegu Gyeongbuk Institute for Science and Technology, Daegu 42988, South Korea.
  • 4 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
  • 5 Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
  • 6 Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
  • 7 Massachusetts General Hospital Frontotemporal Disorders Unit, Gerontology Research Unit, and Alzheimer's Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129.
  • 8 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02114.
PMID: 37043533 DOI: 10.1073/pnas.2217864120
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.

Keywords

Alzheimer’s disease; Cdk5; neurodegenerative disease; tauopathy.

Figures
Products