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TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease

Cyclin-dependent kinase 5 (Cdk5) is a member of the serine-threonine kinase family of cyclin-dependent kinases. Cdk5 is critical to normal mammalian nervous system development and plays important regulatory roles in multiple cellular functions. Recent evidence indicates that Cdk5 is inappropriately...

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Autores principales: Binukumar, BK, Pant, Harish C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Medknow Publications & Media Pvt Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904445/
https://www.ncbi.nlm.nih.gov/pubmed/27335538
http://dx.doi.org/10.4103/1673-5374.182681
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author Binukumar, BK
Pant, Harish C.
author_facet Binukumar, BK
Pant, Harish C.
author_sort Binukumar, BK
collection PubMed
description Cyclin-dependent kinase 5 (Cdk5) is a member of the serine-threonine kinase family of cyclin-dependent kinases. Cdk5 is critical to normal mammalian nervous system development and plays important regulatory roles in multiple cellular functions. Recent evidence indicates that Cdk5 is inappropriately activated in several neurodegenerative conditions, including Parkinson's disease (PD). 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. During neurotoxicity, p35 is cleaved to form p25. Binding of p25 with Cdk5 leads deregulation of Cdk5 resulting in number of neurodegenerative pathologies. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Here we show that inhibition of p25/Cdk5 hyperactivation through TFP5/TP5, truncated 24-aa peptide derived from the Cdk5 activator p35 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 inhibition of Cdk5/p25-hyperactivation by TFP5/TP5 peptide, which identifies Cdk5/p25 as a potential therapeutic target to reduce neurodegeneration in PD.
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spelling pubmed-49044452016-06-22 TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease Binukumar, BK Pant, Harish C. Neural Regen Res Invited Review Cyclin-dependent kinase 5 (Cdk5) is a member of the serine-threonine kinase family of cyclin-dependent kinases. Cdk5 is critical to normal mammalian nervous system development and plays important regulatory roles in multiple cellular functions. Recent evidence indicates that Cdk5 is inappropriately activated in several neurodegenerative conditions, including Parkinson's disease (PD). 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. During neurotoxicity, p35 is cleaved to form p25. Binding of p25 with Cdk5 leads deregulation of Cdk5 resulting in number of neurodegenerative pathologies. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Here we show that inhibition of p25/Cdk5 hyperactivation through TFP5/TP5, truncated 24-aa peptide derived from the Cdk5 activator p35 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 inhibition of Cdk5/p25-hyperactivation by TFP5/TP5 peptide, which identifies Cdk5/p25 as a potential therapeutic target to reduce neurodegeneration in PD. Medknow Publications & Media Pvt Ltd 2016-05 /pmc/articles/PMC4904445/ /pubmed/27335538 http://dx.doi.org/10.4103/1673-5374.182681 Text en Copyright: © Neural Regeneration Research http://creativecommons.org/licenses/by-nc-sa/3.0 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
spellingShingle Invited Review
Binukumar, BK
Pant, Harish C.
TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease
title TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease
title_full TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease
title_fullStr TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease
title_full_unstemmed TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease
title_short TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease
title_sort tfp5/tp5 peptide provides neuroprotection in the mptp model of parkinson's disease
topic Invited Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904445/
https://www.ncbi.nlm.nih.gov/pubmed/27335538
http://dx.doi.org/10.4103/1673-5374.182681
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