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Published on: April 24, 2021
CDK5-mediated tau accumulation triggers methamphetamine-induced neuronal apoptosis via endoplasmic
Ning Xiao1, Fu Zhang2, Bofeng Zhu3
1School of Forensic Medicine, Southern Medical University, Guangzhou 510515, China; Yiling Hospital of Yichang, Hubei, 443000, China.
Abstract:
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.
Insights
Methamphetamine (METH) exposure triggers neuronal apoptosis by increasing phosphorylated Tau protein levels. Blocking CDK5 kinase activity mitigates this effect, suggesting a pathway involving Tau phosphorylation and endoplasmic reticulum stress.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Methamphetamine (METH) is known to induce apoptosis in neuronal cells.
- The precise mechanisms underlying METH-induced neuronal apoptosis are not fully understood.
- Accumulation of phosphorylated Tau protein is linked to neurotoxic pathways and neuronal apoptosis.
Purpose of the Study:
- To investigate the role of Tau protein in methamphetamine-induced neuronal apoptosis.
- To elucidate the molecular mechanisms connecting METH exposure, Tau phosphorylation, and neuronal cell death.
Main Methods:
- Western blotting, immunohistochemistry, and immunofluorescence were used to assess phosphorylated Tau (serine 396 and threonine 231) expression in SH-SY5Y cells and rat hippocampus.
- Expression levels of ubiquitination proteins, proteasome degradation pathway intermediates (CD3-δ), phosphorylated PERK (pPERK), and caspase-12 were measured.
- Cyclin-dependent kinase 5 (CDK5) expression was inhibited using siRNA or virus transfection to study its regulatory role.
Main Results:
- METH exposure significantly increased phosphorylated Tau protein levels in vitro and in vivo.
- Silencing CDK5 expression blocked METH-induced upregulation of phosphorylated Tau, ubiquitination proteins, and CD3-δ.
- METH exposure elevated pPERK and caspase-12 levels, which were suppressed by CDK5 silencing, indicating reduced endoplasmic reticulum stress and apoptosis.
Conclusions:
- Methamphetamine impairs the endoplasmic reticulum-associated degradation (ERAD) pathway, leading to neuronal apoptosis via endoplasmic reticulum stress.
- Abnormal CDK5-regulated Tau phosphorylation is a key mediator in METH-induced neuronal apoptosis.
- Blocking CDK5 expression can mitigate METH-induced neuronal apoptosis, offering a potential therapeutic target.
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