Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5

Kesavapany, Sashi; Zheng, Yali; Amin, Niranjana D.; Pant, Harish C.

doi:10.1002/biot.200700057

Cited by 36 publications

(34 citation statements)

References 43 publications

(39 reference statements)

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“…CIP is a 126-mer artificial peptide containing p35 , which inhibits Cdk5 specifically and potently by blocking Cdk5/p25 complex formation when expressed endogenously (Kesavapany et al, 2007). Transduction of TAT-CIP fully suppressed both early and late activations of Cdc25A, Cdc25B and Cdc25C induced by Ab 1-42 in rat primary cortical neurons ( Fig.…”

Section: Resultsmentioning

confidence: 96%

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

Chang

Vincent

Shah

2012

Journal of Cell Science

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SummaryAberrant activation of cell cycle proteins is believed to play a critical role in Alzheimer's disease (AD) pathogenesis; although, the molecular mechanisms leading to their activation in diseased neurons remain elusive. The goal of this study was to investigate the mechanistic link between Cdk5 deregulation and cell cycle re-activation in b-amyloid 1-42 (Ab )-induced neurotoxicity. Using a chemical genetic approach, we identified Cdc25A, Cdc25B and Cdc25C as direct Cdk5 substrates in mouse brain lysates. We show that deregulated Cdk5 directly phosphorylates Cdc25A, Cdc25B and Cdc25C at multiple sites, which not only increases their phosphatase activities but also facilitates their release from 14-3-3 inhibitory binding. -treated primary cortical neurons, emphasizing a major role of Cdk5 in the activation of Cdc25 isoforms and Cdks in AD pathogenesis. These results were further confirmed in human AD clinical samples, which had higher Cdc25A, Cdc25B and Cdc25C activities that were coincident with increased Cdk5 activity, as compared to age-matched controls. Inhibition of Cdk5 confers the highest neuroprotection against Ab 1-42 toxicity, whereas inhibition of Cdc25 isoforms was partially neuroprotective, further emphasizing a decisive role of Cdk5 deregulation in cell-cycle-driven AD neuronal death.

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Section: Resultsmentioning

confidence: 96%

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

Chang

Vincent

Shah

2012

Journal of Cell Science

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“…It reduces Tau hyperphosphorylation and protects transfected HEK cells and neurons from apoptosis induced by Cdk5-p25 (23,27,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). To produce a smaller and more effective inhibitory peptide of Cdk5-p25 for potential therapeutic use, we designed and constructed five short peptides in GST vectors, as shown in Fig.…”

Section: Identification Of Cdk5-inhibitory Peptides Derived From P35-mentioning

confidence: 99%

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

Zheng

Amin

et al. 2010

Journal of Biological Chemistry

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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 A␤ 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 A␤ 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 A␤(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.The activity of Cdk5, a multifunctional serine/threonine kinase, is critical for neuronal development and synaptic activity; it sustains neurite outgrowth, neuronal migration, cortical lamination, and survival (1-9). Its activity depends on the binding of its neuron-specific, cyclin-related activators, p35 and p39 (10, 11). Cdk5 has also been implicated as a key player in learning and memory (12-15).Normally, Cdk5 activity is tightly regulated, but under conditions of neuronal stress, it is deregulated, leading to hyperactivity, neuronal pathology, and cell death. Accordingly, Cdk5 has been implicated in certain neurodegenerative disorders, such as AD.2 A model of the role of Cdk5 in neurodegeneration suggests that a stress-induced influx of calcium ions into neurons activates calpain, a Ca 2ϩ -activated protease, which cleaves p35 into p25 and a p10 fragment. p25, in turn, forms a more stable Cdk5-p25 hyperactive complex, which hyperphosphorylates Tau and induces cell death (16 -21). Indeed, increased levels of p25 and Cdk5 activity have been reported in AD brains. The finding that p25 may be toxic comes from studies of cortical neurons treated with ␤-amyloid (A␤), a key marker of AD pathology, where p35 is converted to p25 accompanied by activated Cdk5, Tau hyperphosphorylation, and apoptosis (22,23).Expression of the Cdk5-p25 complex seems to be primarily responsible for the Tau pathology ...

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“…Here,E18 cortical neurons stressed by toxic Abeta display an AD phenotype, hyperactive Cdk5/ p25, hyperphosphorylated tau and neurofilaments, Abeta accumulation and apoptosis. These effects are reduced when cells are incubated in different concentrations of p5 or CIP [11,29,32]. The specificity of peptide inhibition was dramatic; whereas Cdk5/p25 activity was inhibited; Cdk5/p35 activity was unaffected as were the activities of cyclin dependent kinases [32].…”

Section: P35-derived Peptides As Therapeutic Candidates For Neurodegementioning

confidence: 99%

“…In the adult, however, Cdk5/p35 is restively more stable since neither site is phosphorylated as p35 acts to bundle microtubules and actin [6,7]. These regulatory options have profound effects on the role of Cdk5 in health and disease [8][9][10][11] (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

“…It is intriguing that in several neurodegenerative disorders (AD, ALS, PD, HD) a hyperactive Cdk5 is detected in the brain at autopsy [6,7] and has been shown to be upstream of the pathways leading to plaques, tangles and inflammation in cultured neurons and model mice [8][9][10][11]. It does so when p35 is not phosphorylated and has been cleaved due to neuronal insults increasing intracellular calcium concentration inducing activation of calpain and cleavage into the myristolated p10 fragment and p25, a deregulated hyperactive Cdk5 [12].…”

Section: Introductionmentioning

confidence: 99%

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Peptides Derived from Neuronal Cell Cycle like Kinase 5 Activator p35, in Neurodegeneration; Pathology and Therapy

Grant¹,

Bhaskar²,

Binukumar³

et al. 2017

J Alzheimers Dis Parkinsonism

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Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5

Cited by 36 publications

References 43 publications

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

Peptides Derived from Neuronal Cell Cycle like Kinase 5 Activator p35, in Neurodegeneration; Pathology and Therapy

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