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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

Scheme of CDK5 signaling pathway involved in Tau phosphorylation. This draw shows the CDK5 signaling pathway describing direct and indirect Tau phosphorylation by CDK5.
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Figure 1: Scheme of CDK5 signaling pathway involved in Tau phosphorylation. This draw shows the CDK5 signaling pathway describing direct and indirect Tau phosphorylation by CDK5.

Mentions: In AD and other tauopathies such as progressive supranuclear palsy (PSP) and frontotemporal dementia associated with parkinsonism linked to chromosome 17, a phenomenon of abnormal Tau hyperphosphorylation or phosphorylation is responsible for a set of alterations, such as axonal transport and mitochondrial and lysosomal dysfunction, among other functions associated with MTs, that can lead to neuronal degeneration (Avila et al., 2004; Iqbal et al., 2009). Upon the abnormal action of kinases and phosphatases, Tau dissociates from MTs and accumulates in the cytosol in packages of the abnormal PHFs, which in turn aggregate to form NFTs (Grundke-Iqbal et al., 1986; Anderton et al., 1995; Mandelkow et al., 2007) (Figure 1). The conditions that facilitate the aggregation and the formation of these structures are still unknown, but studies on the cellular context involved in this phenomenon are vitally important.


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)

Scheme of CDK5 signaling pathway involved in Tau phosphorylation. This draw shows the CDK5 signaling pathway describing direct and indirect Tau phosphorylation by CDK5.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Scheme of CDK5 signaling pathway involved in Tau phosphorylation. This draw shows the CDK5 signaling pathway describing direct and indirect Tau phosphorylation by CDK5.
Mentions: In AD and other tauopathies such as progressive supranuclear palsy (PSP) and frontotemporal dementia associated with parkinsonism linked to chromosome 17, a phenomenon of abnormal Tau hyperphosphorylation or phosphorylation is responsible for a set of alterations, such as axonal transport and mitochondrial and lysosomal dysfunction, among other functions associated with MTs, that can lead to neuronal degeneration (Avila et al., 2004; Iqbal et al., 2009). Upon the abnormal action of kinases and phosphatases, Tau dissociates from MTs and accumulates in the cytosol in packages of the abnormal PHFs, which in turn aggregate to form NFTs (Grundke-Iqbal et al., 1986; Anderton et al., 1995; Mandelkow et al., 2007) (Figure 1). The conditions that facilitate the aggregation and the formation of these structures are still unknown, but studies on the cellular context involved in this phenomenon are vitally important.

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