Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

Abstract

Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity.

Co‐administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats

“…We have previously shown that binge METH decreases the levels of parkin by approximately 42‐48% in striatal synaptosomes (Moszczynska and Yamamoto ) and that parkin overexpression in the nigrostriatal system protects against METH neurotoxicity in adult rats (Liu et al . ). In this study, METH alone, but not BA alone, significantly decreased parkin immunoreactivity in striatal synaptosomal preparations at 1 h after METH; however, the 28%‐deficit in parkin was not sufficient to trigger degeneration of monoaminergic terminals in adolescent rat striatum.…”

Reduced expression of PARK2 in manganese-exposed smelting workers

“…Literature data also show that the cell-permeable Parkin can compensate for intrinsic limitations in the Parkin response and provide a therapeutic strategy to augment Parkin activity in vivo (Duong et al, 2014). Toxicologically, induction of Parkin expression can protect striatal dopaminergic terminals against methamphetamine (METH)-induced neurotox-icity (Liu et al, 2013a). Logically, a reduction in Parkin expression, as observed in this study, could weaken the protective effect of Parkin in the pathoetiology of Parkinson’s disease or related disorders.…”

Disease-Toxicant Interactions in Parkinson’s Disease Neuropathology

“…[125]. Conversely, over-expression of Parkin protects rat dopaminergic neurons from the toxic effects of acute methamphetamine, in vivo [126]. Future studies are necessary in order to examine whether genetic variability in Parkin and other UPS proteins renders the individual more susceptible to dopaminergic cell damage resulting from methamphetamine use.…”