A 24-residue peptide (p5), derived from p35, the Cdk5 neuronal activator, specifically inhibits Cdk5-p25 hyperactivity and tau hyperphosphorylation.
The activity of Cdk5-p35 is tightly regulated in the developing and mature nervous system. Stress-induced cleavage of the activator p35 to p25 and a p10 N-terminal domain induces deregulated Cdk5 hyperactivity and perikaryal aggregations of hyperphosphorylated Tau and neurofilaments, pathogenic hallmarks in neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, respectively. Previously, we identified a 125-residue truncated fragment of p35 called CIP that effectively and specifically inhibited Cdk5-p25 activity and Tau hyperphosphorylation induced by Aβ peptides in vitro, in HEK293 cells, and in neuronal cells. Although these results offer a possible therapeutic approach to those neurodegenerative diseases assumed to derive from Cdk5-p25 hyperactivity and/or Aβ induced pathology, CIP is too large for successful therapeutic regimens. To identify a smaller, more effective peptide, in this study we prepared a 24-residue peptide, p5, spanning CIP residues Lys(245)-Ala(277). p5 more effectively inhibited Cdk5-p25 activity than did CIP in vitro. In neuron cells, p5 inhibited deregulated Cdk5-p25 activity but had no effect on the activity of endogenous Cdk5-p35 or on any related endogenous cyclin-dependent kinases in HEK293 cells. Specificity of p5 inhibition in cortical neurons may depend on the p10 domain in p35, which is absent in p25. Furthermore, we have demonstrated that p5 reduced Aβ(1-42)-induced Tau hyperphosphorylation and apoptosis in cortical neurons. These results suggest that p5 peptide may be a unique and useful candidate for therapeutic studies of certain neurodegenerative diseases.
Zheng
Ya-Li
YL
Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Amin
Niranjana D
ND
Hu
Ya-Fang
YF
Rudrabhatla
Parvathi
P
Shukla
Varsha
V
Kanungo
Jyotshnabala
J
Kesavapany
Sashi
S
Grant
Philip
P
Albers
Wayne
W
Pant
Harish C
HC
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000737:chemistry*; D051360:Cyclin-Dependent Kinase 5 / Q000737:chemistry*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D051381:Rats; D014404:Tubulin / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*
D048868:Adaptor Proteins, Signal Transducing; C500695:CDCA5 protein, human; C492235:Cdk5r1 protein, rat; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C118136:TPPP protein, human; D014404:Tubulin; C553404:p5 protein, human; C553403:p5 protein, rat; D016875:tau Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495907:Cdk5 protein, rat