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Published on: January 7, 2014
The parkinsonian toxin MPTP: action and mechanism
Serge Przedborski1, Vernice Jackson-Lewis, Ruth Djaldetti
1Neuroscience 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.
Abstract:
MPTP causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinson's 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 MPTP's 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.
Insights
MPTP neurotoxicity damages dopamine neurons by inhibiting ATP production and increasing oxidative stress, leading to Parkinson's disease-like pathology. This cascade involves mitochondrial dysfunction and energy failure, implicating similar mechanisms in Parkinson's disease pathogenesis.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc).
- The MPTP mouse model mimics key aspects of PD pathology, offering insights into neurodegenerative mechanisms.
Purpose of the Study:
- To elucidate the molecular mechanisms by which MPTP induces dopaminergic neurotoxicity.
- To investigate the role of oxidative stress, mitochondrial dysfunction, and energy failure in MPTP-induced neuronal damage.
Main Methods:
- Systemic administration of MPTP to induce neurotoxicity.
- Analysis of metabolite accumulation (MPP+) within SNpc DA neurons.
- Assessment of ATP production, superoxide radical formation, and peroxynitrite generation.
- Evaluation of protein nitration, specifically tyrosine hydroxylase (TH) inactivation.
- Investigation of DNA damage and poly(ADP-ribose) polymerase (PARP) activation.
Main Results:
- MPTP's metabolite, MPP+, accumulates in SNpc DA neurons, inhibiting mitochondrial ATP production and generating superoxide radicals.
- Superoxide radicals react with nitric oxide (NO) to form peroxynitrite, causing protein oxidation/nitration and DNA damage.
- Tyrosine hydroxylase (TH), crucial for dopamine synthesis, is inactivated by nitration.
- DNA nicking activates PARP, further depleting ATP and exacerbating energy failure.
- MPTP neurotoxicity involves a cascade of mitochondrial respiration deficit, oxidative stress, and energy failure.
Conclusions:
- MPTP-induced neurotoxicity results from a complex interplay of mitochondrial dysfunction, oxidative stress, and energy depletion.
- The findings support the MPTP mouse model as relevant for studying Parkinson's disease pathogenesis.
- Similar molecular pathways may contribute to the neurodegeneration observed in human Parkinson's disease.
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