The parkinsonian toxin MPTP: action and mechanism

Article type: Research Article

Authors: Przedborski, Serge^; | Jackson-Lewis, Vernice | Djaldetti, Ruth | Liberatore, Gabriel | Vila, Miquel | Vukosavic, Slobodanka | Almer, Gabrielle

Affiliations: Neuroscience Research, Movement Disorder Division, Department of Neurology, Columbia University, New York, NY, USA Neuroscience Research, Movement Disorder Division, Department of Neurology, Columbia University, New York, NY, USA | Department of Pathology, Columbia University, New York, NY, USA

Note: [] Corresponding author: Dr. Serge Przedborski, Departments of Neurology and Pathology, BB-307, Columbia University, 650 West 168th Street, New York, NY 10032, USA. Tel.: +1 212 305 1540; Fax: +1 212 305 5450; E-mail: [email protected]

Abstract: MPTP causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinsons disease (PD). After sys-temic administration of MPTP, its active metabolite, MPP + , accumulates within SNpc DA neurons, where it inhibits ATP production and stim-ulates superoxide radical formation. The produced superoxide radicals react with nitric oxide (NO) to produce peroxynitrite, a highly reactive tissue-damaging species that damages proteins by oxidation and nitration. Only selected proteins appear nitrated, and among these, is found tyrosine hydroxylase (TH), the rate limiting enzyme in DA synthesis. The process of nitration inactivates TH and, consequently dopamine pro-duction. Peroxynitrite also nicks DNA, which, in turn, activates poly(ADP-ribose) polymerase (PARP). PARP activation consumes ATP, and thus acutely depletes cell energy stores. This latter event aggravates the preexisting energy failure due to MPP + -induced mitochondrial respira-tion blockade and precipitates cell death. Altogether, these findings support the view that MPTPs deleterious cascade of events include mito-chondrial respiration deficit, oxidative stress, and energy failure. Because of the similarity between the MPTP mouse model and PD, it is tempting to propose that a similar scenario applies to the pathogenesis of PD.

Keywords: Free radicals, MPTP, neurodegeneration, NO, Parkinsons disease, poly(ADP-ribose) polymerase, tyrosine hydroxylase

Journal: Restorative Neurology and Neuroscience, vol. 16, no. 2, pp. 135-142, 2000