A peptide derived from cyclin‐dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells

Zheng, Yaâli; Li, BingâSheng; Amin, Niranjana D.; Albers, Wayne; Pant, Harish C.

doi:10.1046/j.1432-1033.2002.03133.x

Cited by 74 publications

(88 citation statements)

References 32 publications

(51 reference statements)

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“…Of particular importance are cdk5 and mutant Tau (mTau), as demonstrated by the fact that either modulation of cdk5 complex activity or mutant TauP301L expression leads to alleviation of the transformed phenotype. In concordance with these observations, cdk5 inhibitors were found to reduce Tau phosphorylation and apoptosis in neurons (9,12,13). A role of the cdk5/p35 complex in the genetic etiology of early onset AD was recently suggested (14).…”

supporting

confidence: 54%

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Luo

Dou

Rodina

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

253

226

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Neurodegeneration, a result of multiple dysregulatory events, is a lengthy multistep process manifested by accrual of mutant variants and abnormal expression, posttranslational modification, and processing of certain proteins. Accumulation of these dysregulated processes requires a mechanism that maintains their functional stability and allows the evolution of the neurodegenerative phenotype. In malignant cells, the capacity to buffer transformation has been attributed to heat-shock protein 90 (Hsp90). Although normal proteins seem to require limited assistance from the chaperone, their aberrant counterparts seem to be highly dependent on Hsp90. Whereas enhanced Hsp90 affinity for mutated or functionally deregulated client proteins has been observed for several oncoproteins, it is unknown whether Hsp90 plays a similar role for neuronal proteins and thus maintains and facilitates the transformed phenotype in neurodegenerative diseases. Tauopathies are neurodegenerative diseases characterized by aberrant phosphorylation and/or expression of Tau protein, leading to a timedependent accumulation of Tau aggregates and subsequent neuronal death. Here, we show that the stability of p35, a neuronal protein that activates cyclin-dependent protein kinase 5 through complex formation leading to aberrant Tau phosphorylation, and that of mutant but not WT Tau protein is maintained in tauopathies by Hsp90. Inhibition of Hsp90 in cellular and mouse models of tauopathies leads to a reduction of the pathogenic activity of these proteins and results in elimination of aggregated Tau. The results identify important roles played by Hsp90 in maintaining and facilitating the degenerative phenotype in these diseases and provide a common principle governing cancer and neurodegenerative diseases.cyclin-dependent protein kinase 5 ͉ neurodegeneration ͉ Tau

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supporting

confidence: 54%

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Luo

Dou

Rodina

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

253

226

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“…Human embryo kidney cells (HEK293) were grown as described previously (27). In these experiments, HEK293 cells on day 1 or neurons on day 5 were transfected with or without Myc-p5-GFP using Lipofectamine 2000 following the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Western Blot Analysis-Western blot analysis was performed as described previously (27). In brief, an equal amount of total protein (20 g/lane) was resolved on a 4 -20% SDS-polyacrylamide gel and blotted onto a polyvinylidene difluoride membrane.…”

Section: Methodsmentioning

confidence: 99%

“…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%

“…Our approach to this problem, however, is based on earlier studies, where we identified a peptide of 125 amino acid residues of p35 (CIP) that inhibited Cdk5-p25 activity and rescued cortical neurons from A␤-induced apoptosis without affecting Cdk5-p35 activity (27). This approach might prove to be a more effective way to suppress deregulated Cdk5-p25 hyperactivity inducing neurodegenerative pathology.…”

mentioning

confidence: 99%

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

Kesavapany

Zheng

Amin

et al. 2007

Biotechnology Journal

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Normal Cdk5 activity, conferred mainly by association with its primary activator p35, is critical for normal function of the cell and must be tightly regulated. During neurotoxicity, p35 is cleaved to form p25, which becomes a potent and mislocalized hyperactivator of Cdk5, resulting in a deregulation of Cdk5 activity. p25 levels have been found to be elevated in Alzheimer's disease (AD) brain and overexpression of p25 in a transgenic mouse results in the formation of phosphorylated tau, neurofibrillary tangles and cognitive deficits that are pathological hallmarks of AD. p25/Cdk5 also hyperphosphorylates neurofilament proteins that constitute pathological hallmarks found in Parkinson's disease and amyotrophic lateral sclerosis. The selective targeting of p25/Cdk5 activity without affecting p35/Cdk5 activity has been unsuccessful. In this review we detail our recent studies of selective p25/Cdk5 inhibition without affecting p35/Cdk5 or mitotic Cdk activities. We found that a further truncation of p25 to yield a Cdk5 inhibitory peptide (CIP) can specifically inhibit p25/Cdk5 activity in transfected HEK cells and primary cortical neurons. CIP was able to reduce tau hyperphosphorylation and neuronal death induced caused by p25/Cdk5 and further studies with CIP may develop a specific Cdk5 inhibition strategy in the treatment of neurodegeneration.

show abstract

A peptide derived from cyclin‐dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells

Cited by 74 publications

References 32 publications

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

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

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

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