Parkin protects against tyrosinase-mediated dopamine neurotoxicity by suppressing stress-activated protein kinase pathways

Takafumi Hasegawa, Angela Treis, Nadja Patenge, Fabienne C. Fiesel, Wolfdieter Springer, Philipp J. Kahle

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Parkinson's disease (PD) motor symptoms are caused by degeneration of nigrostriatal dopaminergic (DAergic) neurons. The most common causes of hereditary PD are mutations in the PARKIN gene. The ubiquitin ligase parkin has been shown to mediate neuroprotection in cell culture and in vivo, but the molecular mechanisms are not well understood. We investigated the effects of parkin in a human SH-SY5Y neuroblastoma cell culture model of PD, in which transcriptional induction of the enzyme tyrosinase causes a neurotoxic overproduction of cellular DA and its oxidative metabolites. Tyrosinase induction caused formation of reactive oxygen species in the cytosol and mitochondria, and neurotoxicity via activation of apoptotic stress-activated protein kinases and caspase 3. Stable transfection of wild-type parkin suppressed tyrosinase-induced apoptosis, and PD-associated mutations abolished the neuroprotective effect of parkin. Expression of wild-type parkin did not affect reactive oxygen species production, but attenuated the tyrosinase-induced activation of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase as well as their cognate mitogen-activated protein kinase kinases. PD-associated mutations differentially affected the anti-apoptotic signaling of parkin. Thus, parkin contributes to DAergic neuroprotection by suppression of apoptotic stress-activated protein kinase pathways.

Original languageEnglish (US)
Pages (from-to)1700-1715
Number of pages16
JournalJournal of neurochemistry
Volume105
Issue number5
DOIs
StatePublished - Jun 2008

Keywords

  • Apoptosis
  • Dopamine
  • Neurotoxicity
  • Parkin
  • Stress-activated protein kinases
  • Tyrosinase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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