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Updated: Jun 4, 2026
Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein
Published on: July 29, 2022
Chronic exposure to manganese decreases striatal dopamine turnover in human alpha-synuclein transgenic mice
T M Peneder1, P Scholze, M L Berger
1Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
Abstract:
Interaction of genetic and environmental factors is likely involved in Parkinson's disease (PD). Mutations and multiplications of alpha-synuclein (α-syn) cause familial PD, and chronic manganese (Mn) exposure can produce an encephalopathy with signs of parkinsonism. We exposed male transgenic C57BL/6J mice expressing human α-syn or the A53T/A30P doubly mutated human α-syn under the tyrosine hydroxylase promoter and non-transgenic littermates to MnCl₂-enriched (1%) or control food, starting at the age of 4 months. Locomotor activity was increased by Mn without significant effect of the transgenes. Mice were sacrificed at the age of 7 or 20 months. Striatal Mn was significantly increased about three-fold in those exposed to MnCl₂. The number of tyrosine hydroxylase positive substantia nigra compacta neurons was significantly reduced in 20 months old mice (-10%), but Mn or transgenes were ineffective (three-way ANOVA with the factors gene, Mn and age). In 7 months old mice, striatal homovanillic acid (HVA)/dopamine (DA) ratios and aspartate levels were significantly increased in control mice with human α-syn as compared to non-transgenic controls (+17 and +11%, respectively); after Mn exposure both parameters were significantly reduced (-16 and -13%, respectively) in human α-syn mice, but unchanged in non-transgenic animals and mice with mutated α-syn (two-way ANOVA with factors gene and Mn). None of the parameters were changed in the 20 months old mice. Single HVA/DA ratios and single aspartate levels significantly correlated across all treatment groups suggesting a causal relationship between the rate of striatal DA metabolism and aspartate release. In conclusion, under our experimental conditions, Mn and human α-syn, wild-type and doubly mutated, did not interact to induce PD-like neurodegenerative changes. However, Mn significantly and selectively interacted with human wild-type α-syn on indices of striatal DA neurotransmission, the neurotransmitter most relevant to PD.
Insights
Manganese exposure and alpha-synuclein mutations did not cause Parkinson's disease-like neurodegeneration in mice. However, manganese interacted with wild-type alpha-synuclein, affecting dopamine neurotransmission.
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- Parkinson's disease (PD) involves genetic and environmental factors.
- Alpha-synuclein (α-syn) mutations cause familial PD.
- Manganese (Mn) exposure can induce parkinsonism.
Purpose of the Study:
- To investigate the combined effects of genetic α-syn variations and chronic Mn exposure on PD-like pathology.
- To determine if Mn and α-syn interact to cause neurodegeneration in a mouse model.
Main Methods:
- Transgenic mice expressing human wild-type or mutated α-syn were exposed to Mn or control diets.
- Locomotor activity, striatal Mn levels, neuron counts, and neurotransmitter metabolites (HVA/DA) were analyzed.
- Analyses included three-way and two-way ANOVAs across different ages (7 and 20 months).
Main Results:
- Mn exposure increased locomotor activity but did not cause significant neurodegeneration in substantia nigra neurons.
- Striatal Mn levels increased significantly with Mn exposure.
- In 7-month-old mice, Mn exposure reduced striatal HVA/DA ratios and aspartate levels specifically in mice with wild-type human α-syn.
Conclusions:
- Under these conditions, Mn and α-syn (wild-type or mutated) did not induce PD-like neurodegenerative changes.
- Mn selectively interacted with wild-type human α-syn, impacting dopamine neurotransmission indices.
- A correlation was observed between striatal dopamine metabolism and aspartate release.
