Limits...
p38 MAPK and PI3K/AKT Signalling Cascades inParkinson's Disease.

Jha SK, Jha NK, Kar R, Ambasta RK, Kumar P - Int J Mol Cell Med (2015)

Bottom Line: These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD.Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades.In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi, India.

ABSTRACT
Parkinson's disease (PD) is a chronic neurodegenerative condition which has the second largest incidence rate among all other neurodegenerative disorders barring Alzheimer's disease (AD). Currently there is no cure and researchers continue to probe the therapeutic prospect in cell cultures and animal models of PD. Out of the several factors contributing to PD prognosis, the role of p38 MAPK (Mitogen activated protein-kinase) and PI3K/AKT signalling module in PD brains is crucial because the impaired balance between the pro- apoptotic and anti-apoptotic pathways trigger unwanted phenotypes such as microglia activation, neuroinflammation, oxidative stress and apoptosis. These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD. Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades. In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

No MeSH data available.


Related in: MedlinePlus

Neuroprotective cross-talk involving the cytoprotective PI3K/AKT pathway. AKT when optimally activated by phosphorylation at serine and threonine residues, can interact with a spectrum of molecules to erect an anti- inflammatory (DJ-1 and HIF-1α) and anti- apoptotic (Bcl-2) ambience in vulnerable neurons. In addition, phosphorylated AKT can also promote autophagy via PINK-1 and Parkin. IRS-1 activation takes place via IGF-1/AKT cascade and other AKT targets including p85β and SPRED 1 are known to be downregulated by miR-126 in PD neurons. Activation (green arrows); prevention or suppression (red arrows
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4499569&req=5

Figure 2: Neuroprotective cross-talk involving the cytoprotective PI3K/AKT pathway. AKT when optimally activated by phosphorylation at serine and threonine residues, can interact with a spectrum of molecules to erect an anti- inflammatory (DJ-1 and HIF-1α) and anti- apoptotic (Bcl-2) ambience in vulnerable neurons. In addition, phosphorylated AKT can also promote autophagy via PINK-1 and Parkin. IRS-1 activation takes place via IGF-1/AKT cascade and other AKT targets including p85β and SPRED 1 are known to be downregulated by miR-126 in PD neurons. Activation (green arrows); prevention or suppression (red arrows

Mentions: PI3K/AKT pathway can also play a key role in IGF-mediated cell survival and prevention of apoptosis in MPP+ induced human neuroblastoma SH-EP1 cells. This defensive activity of AKT is principally reliant on the BIO mediated inactivation of GSK-3β, the result of which could imitate the protective influence of IGF-1 in SH-EP1 cells. Interestingly, the IGF-1 potentiated PI3K/AKT activity was found to further down regulate the JNK related apoptotic activity and this negative regulation was reported to be facilitated via AKT-dependent GSK-3β inactivation (Figure 2). Moreover, these results acknowledge that IGF-1 protects SH-EP1 cells from MPP+-induced apoptotic cell mortality via the cytoprotective PI3K/AKT/GSK-3β pathway involving GSK-3β inactivation (66-68). Most recently, it hes been studied in DA neuronal cell systems that upregulation of miR-126 impaired IGF-1 signalling and increased the susceptibility of such systems to 6-OHDA, possibly by stamping down factors involved in IGF-1/PI3K signalling, including its downstream targets p85β, IRS-1, and SPRED1. MicroRNAs (miRs/miRNAs) act as posttranscrip-tional regulators of gene expression and therefore, it is unsurprising that they could be critically modulating pathogenesis in PD. Notably, blocking miR-126 activity increased IGF-1 trophism and thereby combating the cataclysmic events of 6- OHDA. This result strongly ascertain the criticality IGF-1/ PI3K cascade in DA neuron maintenance and also suggests that the higher expression patterns of miR-126 may contribute towards DA neurodegeneration aided by downregulation of IGF-1/PI3K/AKT signalling (69).


p38 MAPK and PI3K/AKT Signalling Cascades inParkinson's Disease.

Jha SK, Jha NK, Kar R, Ambasta RK, Kumar P - Int J Mol Cell Med (2015)

Neuroprotective cross-talk involving the cytoprotective PI3K/AKT pathway. AKT when optimally activated by phosphorylation at serine and threonine residues, can interact with a spectrum of molecules to erect an anti- inflammatory (DJ-1 and HIF-1α) and anti- apoptotic (Bcl-2) ambience in vulnerable neurons. In addition, phosphorylated AKT can also promote autophagy via PINK-1 and Parkin. IRS-1 activation takes place via IGF-1/AKT cascade and other AKT targets including p85β and SPRED 1 are known to be downregulated by miR-126 in PD neurons. Activation (green arrows); prevention or suppression (red arrows
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499569&req=5

Figure 2: Neuroprotective cross-talk involving the cytoprotective PI3K/AKT pathway. AKT when optimally activated by phosphorylation at serine and threonine residues, can interact with a spectrum of molecules to erect an anti- inflammatory (DJ-1 and HIF-1α) and anti- apoptotic (Bcl-2) ambience in vulnerable neurons. In addition, phosphorylated AKT can also promote autophagy via PINK-1 and Parkin. IRS-1 activation takes place via IGF-1/AKT cascade and other AKT targets including p85β and SPRED 1 are known to be downregulated by miR-126 in PD neurons. Activation (green arrows); prevention or suppression (red arrows
Mentions: PI3K/AKT pathway can also play a key role in IGF-mediated cell survival and prevention of apoptosis in MPP+ induced human neuroblastoma SH-EP1 cells. This defensive activity of AKT is principally reliant on the BIO mediated inactivation of GSK-3β, the result of which could imitate the protective influence of IGF-1 in SH-EP1 cells. Interestingly, the IGF-1 potentiated PI3K/AKT activity was found to further down regulate the JNK related apoptotic activity and this negative regulation was reported to be facilitated via AKT-dependent GSK-3β inactivation (Figure 2). Moreover, these results acknowledge that IGF-1 protects SH-EP1 cells from MPP+-induced apoptotic cell mortality via the cytoprotective PI3K/AKT/GSK-3β pathway involving GSK-3β inactivation (66-68). Most recently, it hes been studied in DA neuronal cell systems that upregulation of miR-126 impaired IGF-1 signalling and increased the susceptibility of such systems to 6-OHDA, possibly by stamping down factors involved in IGF-1/PI3K signalling, including its downstream targets p85β, IRS-1, and SPRED1. MicroRNAs (miRs/miRNAs) act as posttranscrip-tional regulators of gene expression and therefore, it is unsurprising that they could be critically modulating pathogenesis in PD. Notably, blocking miR-126 activity increased IGF-1 trophism and thereby combating the cataclysmic events of 6- OHDA. This result strongly ascertain the criticality IGF-1/ PI3K cascade in DA neuron maintenance and also suggests that the higher expression patterns of miR-126 may contribute towards DA neurodegeneration aided by downregulation of IGF-1/PI3K/AKT signalling (69).

Bottom Line: These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD.Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades.In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi, India.

ABSTRACT
Parkinson's disease (PD) is a chronic neurodegenerative condition which has the second largest incidence rate among all other neurodegenerative disorders barring Alzheimer's disease (AD). Currently there is no cure and researchers continue to probe the therapeutic prospect in cell cultures and animal models of PD. Out of the several factors contributing to PD prognosis, the role of p38 MAPK (Mitogen activated protein-kinase) and PI3K/AKT signalling module in PD brains is crucial because the impaired balance between the pro- apoptotic and anti-apoptotic pathways trigger unwanted phenotypes such as microglia activation, neuroinflammation, oxidative stress and apoptosis. These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD. Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades. In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

No MeSH data available.


Related in: MedlinePlus