p25/Cyclin‐dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum‐stressed neurons

Abstract

Dysregulation of cyclin-dependent kinase 5 (Cdk5) by cleavage of its activator p35 to p25 by calpain is involved in the neuronal cell death observed in neurodegenerative disorders, including Alzheimer's disease. However, it is not yet clear how p25/Cdk5 induces cell death, although its cytosolic localization or extended half life are thought to be involved. We show here that endoplasmic reticulum (ER) stress causes the calpaindependent cleavage of p35 to p25 in primary cultured cortical neurons. Generation of p25 occurred at a cell death execution step in ER-stressed neurons. p25 translocated to the nucleus in ER-stressed neurons, whereas p35/Cdk5 was perinuclear in control neurons. Cdk5 inhibitors or dominant-negative Cdk5 suppressed ER stress-induced neuronal cell death. These findings indicate that p25/Cdk5 is a proapoptotic factor that promotes ER stress-induced neuronal cell death in nuclei.

LMTK1/AATYK1 Is a Novel Regulator of Axonal Outgrowth That Acts via Rab11 in a Cdk5-Dependent Manner

“…All experiments were performed according to the guidelines for animal experimentation of Tokyo Metropolitan University (Tokyo, Japan). Brain cortices from embryonic day 17 or 18 mice were dissected and plated in polyethyleneimine-coated dishes or on polyethyleneimine-coated glass coverslips at a density of 5.2 ϫ 10 5 neurons/cm 2 (Saito et al, 2007). Plasmid vectors were introduced into neurons by electroporation with an Amaxa Nucleofector apparatus according to the manufacturer's instructions.…”

Commitment of 1-Methyl-4-phenylpyrinidinium Ion-induced Neuronal Cell Death by Proteasome-mediated Degradation of p35 Cyclin-dependent Kinase 5 Activator

“…The amount of p35 is the major determinant of Cdk5 activity, and it is normally a short-lived protein degraded by the ubiquitin-proteasome pathway (15,16). However, in stressed neurons, the calcium-activated protease calpain cleaves p35 to the more stable and active form, p25 (17)(18)(19)(20)(21). Hyperactivated or mislocalized Cdk5-p25 has been implicated in the pathogenesis of numerous neurodegenerative disorders including PD and Alzheimer disease.…”

Mechanistic Role of Calpains in Postischemic Neurodegeneration

“…Activity of CDK5 kinase is regulated by the binding of one of its activator proteins, p35 or p39, which are cleaved by calpain to form to p25 or p29, respectively (Kusakawa et al, 2000;Patzke and Tsai, 2002). Accumulation of p25 has been shown after excitotoxicity, hypoxia, calcium overload, and ER stress in primary neuronal culture (Lee et al, 2000;Saito et al, 2007), as well as after middle cerebral artery occlusion in vivo (Nath et al, 2000). Similar results have been reported for p29 (Patzke and Tsai, 2002).…”

“…Calpain-mediated truncation of p35 to p25 produces a more stable form of the protein, which is still able to activate CDK5. The CDK5-p25 complex translocates from the cytoplasm to the nucleus, where it appears to play an essential role in neuronal cell death (O'Hare et al, 2005;Saito et al, 2007).…”