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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

Variation in the levels of Tau and pTau after KOis of CDK5, GSK3 β, PP2A, and PP1. K2 was modified, which decreased this value by 100%. The inset in the figure indicates pTau variation compared with the basal condition.
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Figure 3: Variation in the levels of Tau and pTau after KOis of CDK5, GSK3 β, PP2A, and PP1. K2 was modified, which decreased this value by 100%. The inset in the figure indicates pTau variation compared with the basal condition.

Mentions: To examine the sensitivity of the model to variations in different molecular species, KOis were performed that consisted of completely suppressing the activity of the molecular species by reducing the K2 constant (Vmax) to a number very close to zero. It was observed that the model was sensitive to dramatic changes in GSK3β, which decreased pTau levels to 40.5%, and changes in PP2A, which increased pTau levels to 56%. The KOis of CDK5 showed a change in pTau of 13%, and the KOis of PP1 did not alter pTau significantly (Figure 3). These results show that the system is more sensitive to proteins that have little regulation in our model; despite this, the model is stable to 100% variation because the maximum change generated only represented a 56% increase in pTau specifically with the KOis of PP2A.


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)

Variation in the levels of Tau and pTau after KOis of CDK5, GSK3 β, PP2A, and PP1. K2 was modified, which decreased this value by 100%. The inset in the figure indicates pTau variation compared with the basal condition.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Variation in the levels of Tau and pTau after KOis of CDK5, GSK3 β, PP2A, and PP1. K2 was modified, which decreased this value by 100%. The inset in the figure indicates pTau variation compared with the basal condition.
Mentions: To examine the sensitivity of the model to variations in different molecular species, KOis were performed that consisted of completely suppressing the activity of the molecular species by reducing the K2 constant (Vmax) to a number very close to zero. It was observed that the model was sensitive to dramatic changes in GSK3β, which decreased pTau levels to 40.5%, and changes in PP2A, which increased pTau levels to 56%. The KOis of CDK5 showed a change in pTau of 13%, and the KOis of PP1 did not alter pTau significantly (Figure 3). These results show that the system is more sensitive to proteins that have little regulation in our model; despite this, the model is stable to 100% variation because the maximum change generated only represented a 56% increase in pTau specifically with the KOis of PP2A.

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