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Cyclin-dependent kinase 5, a node protein in diminished tauopathy: a systems biology approach.

Castro-Alvarez JF, Uribe-Arias SA, Mejía-Raigosa D, Cardona-Gómez GP - Front Aging Neurosci (2014)

Bottom Line: Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way.In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented.The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Group of Antioquia, Cellular and Molecular Neurobiology Area, Faculty of Medicine, University of Antioquia, Sede de Investigación Universitaria Medellin, Colombia.

ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

No MeSH data available.


Related in: MedlinePlus

Changes in the levels of Tau and pTau in response to SIS of CDK5 and GSK3 β in conditions simulating AD with increased calcium levels and a decrease in phosphatase activity. CDK5 and GSK3β were silenced by 75%. The inset in the graph indicates the decrease in pTau in response to increased calcium.
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Figure 6: Changes in the levels of Tau and pTau in response to SIS of CDK5 and GSK3 β in conditions simulating AD with increased calcium levels and a decrease in phosphatase activity. CDK5 and GSK3β were silenced by 75%. The inset in the graph indicates the decrease in pTau in response to increased calcium.

Mentions: In AD, it has been described that the excitotoxic process, as well as the increase in p25-mediated CDK5 activity and a decrease in the activity of phosphatases, plays a key role in the development of the disease. To simulate a similar condition, calcium concentration was increased by 100-fold, and the activity of both phosphatases was decreased by 50% (Figure 6). Under these conditions, the simulation of the pathological condition significantly increased pTau concentration (46%) (Figure 6). This strong trend toward hyperphosphorylation is consistent with the descriptions of AD where the presence of NFTs and Tau aggregation is a diagnostic criterion and is closely related to the pathogenesis of this dementia.


Cyclin-dependent kinase 5, a node protein in diminished tauopathy: a systems biology approach.

Castro-Alvarez JF, Uribe-Arias SA, Mejía-Raigosa D, Cardona-Gómez GP - Front Aging Neurosci (2014)

Changes in the levels of Tau and pTau in response to SIS of CDK5 and GSK3 β in conditions simulating AD with increased calcium levels and a decrease in phosphatase activity. CDK5 and GSK3β were silenced by 75%. The inset in the graph indicates the decrease in pTau in response to increased calcium.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150361&req=5

Figure 6: Changes in the levels of Tau and pTau in response to SIS of CDK5 and GSK3 β in conditions simulating AD with increased calcium levels and a decrease in phosphatase activity. CDK5 and GSK3β were silenced by 75%. The inset in the graph indicates the decrease in pTau in response to increased calcium.
Mentions: In AD, it has been described that the excitotoxic process, as well as the increase in p25-mediated CDK5 activity and a decrease in the activity of phosphatases, plays a key role in the development of the disease. To simulate a similar condition, calcium concentration was increased by 100-fold, and the activity of both phosphatases was decreased by 50% (Figure 6). Under these conditions, the simulation of the pathological condition significantly increased pTau concentration (46%) (Figure 6). This strong trend toward hyperphosphorylation is consistent with the descriptions of AD where the presence of NFTs and Tau aggregation is a diagnostic criterion and is closely related to the pathogenesis of this dementia.

Bottom Line: Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way.In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented.The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Group of Antioquia, Cellular and Molecular Neurobiology Area, Faculty of Medicine, University of Antioquia, Sede de Investigación Universitaria Medellin, Colombia.

ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.

No MeSH data available.


Related in: MedlinePlus