Parkin protects dopaminergic terminals against methamphetamine neurotoxicity by inducing inclusion formation

Abstract

Viral vector‐mediated delivery of parkin pervents dopaminergic (DAergic) neurodegeneration in Parkinsonˈs disease models. One of the mechanisms underlying parkin neuroprotection is to promote the formation of á‐synuclein inclusions. It is unclear whether parkin protects against methamphetamine (METH)‐induced degeneration of DAergic terminals. Here we investigated whether parkin overexpression protects against METH neurotoxicity and whether the parkin effect is due to the formation of inclusions. Parkin‐containing adeno‐associated viral 2/6 vector was injected into the left substantia nigra in rats with/without METH treatment. Parkin‐immunoreactivity (IR) in the left substantia nigra and striatum was higher than that of right side. A large portion of parkin‐positive DAergic neurons and terminals expressed tyrosine hydroxylase (TH). Animals overerexpressing parkin showed reductions in METH‐induced decrease in TH‐IR in the striatum. Parkin‐mediated neuroprotection was associated with an increase of punctuated á‐synuclein immunostaining in the striatum. These data suggest that parkin overexpression attenuates METH‐induced damage to striatal DAergic terminals, which may be via increasing á‐synuclein inclusions. It also suggests that future clinical applications to prevent METH neurotoxicity might involve the mediation of parkin function. Support: NIH DA023085