Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson's disease.

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer's disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 -hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson's disease.

• Authors: B K Binukumar, Varsha Shukla, Niranjana D Amin, Philip Grant, M Bhaskar, Susan Skuntz, Joseph Steiner, Harish C Pant
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 26 Issue 24 Pg. 4478-91 (Dec 01 2015) ISSN: 1939-4586 [Electronic] United States
• PMID: 26399293 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © 2015 Binukumar et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Chemical References

• Nerve Tissue Proteins
• Neuroprotective Agents
• Peptide Fragments
• neuronal Cdk5 activator (p25-p35)
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Cyclin-Dependent Kinase 5
• Dopamine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Amino Acid Sequence
• Animals
• Cyclin-Dependent Kinase 5 (metabolism)
• Disease Models, Animal
• Dopamine (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Nerve Tissue Proteins (chemistry, pharmacology)
• Neurons (metabolism)
• Neuroprotective Agents (pharmacology)
• Parkinson Disease (drug therapy, metabolism)
• Peptide Fragments (pharmacology)
• Substantia Nigra