Effects of cyclin-dependent kinase-5 activity on apoptosis and tau phosphorylation in immortalized mouse brain cortical cells

2004 ◽  
Vol 76 (1) ◽  
pp. 110-120 ◽  
Author(s):  
Shirley B. Shelton ◽  
Pavan Krishnamurthy ◽  
Gail V.W. Johnson
Keyword(s):  
Mouse Brain ◽  
Tau Phosphorylation ◽  
Cyclin Dependent Kinase ◽  
Cortical Cells ◽  
Cyclin Dependent Kinase 5

Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262

2019 ◽  
Vol 28 (18) ◽  
pp. 3062-3071 ◽  
Author(s):  
Taro Saito ◽  
Toshiya Oba ◽  
Sawako Shimizu ◽  
Akiko Asada ◽  
Koichi M Iijima ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Tau Phosphorylation ◽  
Activation Loop ◽  
Cyclin Dependent Kinase ◽  
Drosophila Model ◽  
Target Sites ◽  
Liver Kinase B1 ◽  
Tau Kinases ◽  
The Brain ◽  
Cyclin Dependent Kinase 5

Abstract Hyperphosphorylation of the microtubule-associated protein tau is associated with many neurodegenerative diseases, including Alzheimer’s disease. Microtubule affinity-regulating kinases (MARK) 1–4 and cyclin-dependent kinase 5 (Cdk5) are tau kinases under physiological and pathological conditions. However, their functional relationship remains elusive. Here, we report a novel mechanism by which Cdk5 activates MARK4 and augments tau phosphorylation, accumulation and toxicity. MARK4 is highly phosphorylated at multiple sites in the brain and in cultured neurons, and inhibition of Cdk5 activity reduces phosphorylation levels of MARK4. MARK4 is known to be activated by phosphorylation at its activation loop by liver kinase B1 (LKB1). In contrast, Cdk5 increased phosphorylation of MARK4 in the spacer domain, but not in the activation loop, and enhanced its kinase activity, suggesting a novel mechanism by which Cdk5 regulates MARK4 activity. We also demonstrated that co-expression of Cdk5 and MARK4 in mammalian cultured cells significantly increased the levels of tau phosphorylation at both Cdk5 target sites (SP/TP sites) and MARK target sites (Ser262), as well as the levels of total tau. Furthermore, using a Drosophila model of tau toxicity, we demonstrated that Cdk5 promoted tau accumulation and tau-induced neurodegeneration via increasing tau phosphorylation levels at Ser262 by a fly ortholog of MARK, Par-1. This study suggests a novel mechanism by which Cdk5 and MARK4 synergistically increase tau phosphorylation and accumulation, consequently promoting neurodegeneration in disease pathogenesis.

scholarly journals Tau Phosphorylation by Cyclin-dependent Kinase 5/p39 during Brain Development Reduces Its Affinity for Microtubules

2003 ◽  
Vol 278 (12) ◽  
pp. 10506-10515 ◽  
Author(s):  
Satoru Takahashi ◽  
Taro Saito ◽  
Shin-ichi Hisanaga ◽  
Harish C. Pant ◽  
Ashok B. Kulkarni
Keyword(s):  
Brain Development ◽  
Tau Phosphorylation ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase 5

scholarly journals Cyclin-Dependent Kinase 5 Regulates Dendritic Spine Formation and Maintenance of Cortical Neuron in the Mouse Brain

2014 ◽  
Vol 26 (3) ◽  
pp. 967-976 ◽  
Author(s):  
Naoki Mita ◽  
Xiaojuan He ◽  
Kodai Sasamoto ◽  
Tomohide Mishiba ◽  
Toshio Ohshima
Keyword(s):  
Cortical Neuron ◽  
Mouse Brain ◽  
Dendritic Spine ◽  
Cyclin Dependent Kinase ◽  
Spine Formation ◽  
Cyclin Dependent Kinase 5
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