CDK5-mediated tau accumulation triggers methamphetamine-induced neuronal apoptosis via endoplasmic reticulum-associated degradation pathway.
Overexposure to methamphetamine (METH) causes apoptosis in a number of cell types, particularly neuronal cells. However, the underlying mechanisms of METH-induced neuronal apoptosis remain to be elucidated. Accumulation of microtubule-associated protein Tau can lead to activation of multiple neurotoxic pathways, which is closely correlated with neuronal apoptosis. The aim of this study was to determine the role of Tau in METH-induced neuronal apoptosis. We determined the expression of two phosphorylated Tau proteins (serine 396 and threonine 231) in the human neuroblastoma SH-SY5Y cells and in the hippocampus of Sprague-Dawley rats treated with vehicle or METH using western blotting, immunohistochemical staining and immunofluorescence staining. We also measured the expression levels of the phosphorylated Tau protein, ubiquitination proteins, the intermediate products of proteasome degradation pathway, CD3-δ (a substrate of proteasome degradation pathway), endoplasmic reticulum stress signal molecule phosphorylated PERK (pPERK), and endoplasmic reticulum stress-specific apoptotic signal molecule caspase-12 in SH-SY5Y cells and in rats after inhibiting the expression of an upstream regulatory factor of phosphorylated Tau protein (CDK5) using siRNA or virus transfection. The results showed that exposure to METH significantly up-regulated the expression of phosphorylated Tau protein in vivo and in vitro and silencing the expression of CDK5 inhibited the up-regulation of phosphorylated Tau induced by METH exposure. METH exposure also significantly increased the expression of ubiquitination protein and CD3-δ and these effects were blocked by CDK5 silencing. In addition, METH exposure significantly elevated the levels of phosphorylated PERK and caspase-12 and these effects were suppressed after CDK5 silencing, which indicates that blockade of CDK5 expression can mitigate METH-induced neuronal apoptosis. These results suggest that METH can impair the endoplasmic reticulum-associated degradation (ERAD) pathway and induce neuronal apoptosis through endoplasmic reticulum stress, which is mainly mediated by abnormal CDK5-regulated Tau phosphorylation.
['Xiao|Ning|N|', 'Zhang|Fu|F|', 'Zhu|Bofeng|B|', 'Liu|Chao|C|', 'Lin|Zhoumeng|Z|', 'Wang|Huijun|H|', 'Xie|Wei-Bing|WB|']
D000818:Animals D017209:Apoptosis D017252:CD3 Complex D053454:Caspase 12 D045744:Cell Line, Tumor D000697:Central Nervous System Stimulants D051360:Cyclin-Dependent Kinase 5 D004305:Dose-Response Relationship, Drug D060746:Endoplasmic Reticulum-Associated Degradation D006624:Hippocampus D006801:Humans D008297:Male D008694:Methamphetamine D009474:Neurons D010766:Phosphorylation D046988:Proteasome Endopeptidase Complex D034622:RNA Interference D017207:Rats, Sprague-Dawley D015398:Signal Transduction D013997:Time Factors D014162:Transfection D054875:Ubiquitination D019892:eIF-2 Kinase D016875:tau Proteins
Apoptosis Methamphetamine (METH) Tau protein Cyclin-dependent kinase-5 (CDK5) Endoplasmic reticulum stress (ER stress)