Effect of Parkin on methamphetamine‐induced α‐synuclein degradation dysfunction in vitro and in vivo

Abstract

Abstract Introduction Methamphetamine (METH) is a psychostimulant drug with complicated neurotoxicity, and abuse of METH is very common. Studies have shown that METH exposure causes alpha‐synuclein (α‐syn) accumulation. However, the mechanism of α‐syn accumulation has not been determined. Methods In this study, we established cell and animal models of METH intoxication to evaluate how METH affects α‐syn expression. In addition, to explore METH‐induced neurotoxicity, we measured the level of Parkin and the phosphorylation levels of α‐syn, Polo‐like kinase 2 (PLK2), the proteasome activity marker CD3δ, and the apoptosis‐related proteins Caspase‐3 and PARP. Parkin is a key enzyme in the ubiquitin–proteasome system. In addition, the effect of Parkin on METH‐induced neurotoxicity was investigated by overexpressing it in vitro and in vivo. Results METH exposure increased polyubiquitin and α‐syn expression, as did MG132. Furthermore, the level of Parkin and the interaction between Parkin and α‐syn decreased after METH exposure. Importantly, the increases in α‐syn expression and neurotoxicity were relieved by Parkin overexpression. Conclusions By establishing stable cell lines and animal models that overexpress Parkin, we confirmed Parkin as an important factor in METH‐induced α‐syn degradation dysfunction in vitro and in vivo. Parkin may be a promising target for the treatment of METH‐induced neurotoxicity.

Keywords

• methamphetamine
• neurotoxicity
• Parkin
• α‐syn