Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism

Allen S. Mandir, Serge Przedborski, Vernice Jackson-Lewis, Zhao Qi Wang, Cynthia M. Simbulan-Rosenthal, Mark E. Smulson, Brian E. Hoffman, Daniel B. Guastella, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticlepeer-review

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes parkinsonism in humans and nonhuman animals, and its use has led to greater understanding of the pathogenesis of Parkinson's disease. However, its molecular targets have not been defined. We show that mice lacking the gene for poly(ADP-ribose) polymerase (PARP), which catalyzes the attachment of ADP ribose units from NAD to nuclear proteins after DNA damage, are dramatically spared from MPTP neurotoxicity. MPTP potently activates PARP exclusively in vulnerable dopamine containing neurons of the substantia nigra. MPTP elicits a novel pattern of poly(ADP-ribosyl)ation of nuclear proteins that completely depends on neuronally derived nitric oxide. Thus, NO, DNA damage, and PARP activation play a critical role in MPTP-induced parkinsonism and suggest that inhibitors of PARP may have protective benefit in the treatment of Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)5774-5779
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number10
DOIs
StatePublished - May 11 1999

ASJC Scopus subject areas

  • General

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