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

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.