Related Experiment Videos
Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter
E Bezard1, C E Gross, M C Fournier
1Basal Gang, CNRS UMR 5541, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université de Bordeaux II, 146 rue Leo Saignat, Bordeaux Cedex, 33076, France.
Abstract:
MPTP has been shown to induce parkinsonism both in human and in nonhuman primates. The precise mechanism of dopaminergic cell death induced following MPTP treatment is still subject to intense debate. MPP+, which is the oxidation product of MPTP, is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter (DAT). In this study, we used mice lacking the DAT by homologous recombination and demonstrated that the MPTP-induced dopaminergic cell loss is dependent on the presence of the DAT. For this we have used tyrosine hydroxylase immunoreactivity (TH-IR) labeling of dopamine cells of the substantia nigra compacta in wild-type, heterozygote, and homozygote mice that were given either saline or MPTP treatments (two ip injections of 30 mg/kg, 10 h apart). Our results show a significant loss of TH-IR in wild type (34.4%), less loss in heterozygotes (22.5%), and no loss in homozygote animals. Thus dopamine cell loss is related to levels of the DAT. These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinson's disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin.
Insights
MPTP causes parkinsonism by damaging dopamine cells, but this damage requires the dopamine transporter (DAT). Mice lacking DAT are protected from MPTP-induced neurodegeneration, highlighting DAT
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in humans and primates.
- The exact mechanism of MPTP-induced dopaminergic cell death is debated.
- MPP+ (1-methyl-4-phenylpyridinium), the toxic metabolite of MPTP, enters dopaminergic neurons via the dopamine transporter (DAT).
Purpose of the Study:
- To investigate the role of the dopamine transporter (DAT) in MPTP-induced dopaminergic neurotoxicity.
- To determine if DAT expression levels correlate with susceptibility to MPTP neurodegeneration.
Main Methods:
- Utilized genetically engineered mice lacking the DAT (homologous recombination).
- Administered MPTP (two injections of 30 mg/kg, 10 hours apart) or saline to wild-type, DAT heterozygote, and DAT homozygote mice.
- Assessed dopaminergic cell loss using tyrosine hydroxylase immunoreactivity (TH-IR) in the substantia nigra compacta.
Main Results:
- Wild-type mice showed a significant loss of TH-IR (34.4%) after MPTP treatment.
- DAT heterozygote mice exhibited a reduced TH-IR loss (22.5%).
- DAT homozygote mice (lacking DAT) displayed no significant loss of TH-IR, indicating protection from MPTP toxicity.
Conclusions:
- MPTP-induced dopaminergic cell loss is critically dependent on the presence and function of the dopamine transporter (DAT).
- These findings elucidate the mechanism of MPTP neurotoxicity and suggest DAT-mediated uptake of neurotoxins may contribute to individual susceptibility in Parkinson's disease.