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Published on: January 7, 2014
Evidence for a dissociation between MPTP toxicity and tyrosinase activity based on congenic mouse strain
K Hofele1, M Sedelis, G W Auburger
1Department of Neurology, Heinrich-Heine-University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
Abstract:
The neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most valuable available models for investigating critical aspects of human Parkinson's disease. In order to analyze the relevance of pigmentation for MPTP sensitivity, we compared C57Bl/6 wild-type mice with the albino mutant C57Bl/6J-Tyr(c-2J) of the same strain. These animals were treated either with systemic MPTP or with saline and were examined in behavioral tests. Seven days after treatment, the contents of dopamine and other monoamines were determined postmortem in the neostriatum and ventral striatum. Furthermore, the numbers of tyrosine hydroxylase-positive cells were counted in the substantia nigra and ventral tegmental area. Open field testing showed that rearing activity was drastically reduced as an acute effect of MPTP in both wild type and mutants; however, subsequent recovery to control levels was faster in wild-type mice. Nest building also indicated strain-dependent effects, since it was delayed only in mutants treated with MPTP. Neurochemically, MPTP led to severe neostriatal dopamine depletions, which did not differ significantly between wild-type (72.9%) and mutant mice (82.1%). Less severe dopamine depletions were also found in the ventral striatum. Histologically, a loss of tyrosine hydroxylase-labeled cells was observed only in the substantia nigra of both wild-type and mutant mice (13.3 and 21.3%, respectively), but not in the ventral tegmental area. Together, our data do not provide evidence that tyrosinase-deficient mice are less affected by MPTP treatment than the comparable wild type, thus arguing strongly against the hypothesis that enhanced MPTP sensitivity in pigmented mouse strains is caused by tyrosinase activity.
Insights
Pigmentation does not affect sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Albino mice showed similar MPTP-induced dopamine depletions and cell loss as pigmented mice, refuting the tyrosinase activity hypothesis.
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a valuable tool for modeling Parkinson's disease.
- Previous hypotheses suggested that pigmentation might influence MPTP sensitivity.
Purpose of the Study:
- To investigate the role of pigmentation in MPTP-induced neurotoxicity.
- To compare MPTP sensitivity between pigmented wild-type mice and albino mutant mice.
Main Methods:
- MPTP or saline treatment in C57Bl/6 wild-type and C57Bl/6J-Tyr(c-2J) albino mice.
- Behavioral testing (open field, nest building).
- Postmortem neurochemical analysis (dopamine, monoamines) and histological assessment (tyrosine hydroxylase-positive cells).
Main Results:
- MPTP acutely reduced rearing activity in both groups, with faster recovery in wild-type mice.
- Nest building was impaired only in MPTP-treated albino mutants.
- MPTP caused significant dopamine depletions in the neostriatum and ventral striatum, with no significant strain differences.
- Loss of tyrosine hydroxylase-positive cells occurred in the substantia nigra but not the ventral tegmental area, with similar severity in both strains.
Conclusions:
- Tyrosinase-deficient albino mice are not less susceptible to MPTP neurotoxicity than pigmented wild-type mice.
- These findings do not support the hypothesis that tyrosinase activity contributes to MPTP sensitivity in pigmented mice.
