title: Chronic exposure to manganese decreases striatal dopamine turnover in human alpha-synuclein transgenic mice.
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.
authors.affiliation: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: T M
authors.initials: TM
authors.lastname: Peneder
authors.forename: P
authors.initials: P
authors.lastname: Scholze
authors.forename: M L
authors.initials: ML
authors.lastname: Berger
authors.forename: H
authors.initials: H
authors.lastname: Reither
authors.forename: G
authors.initials: G
authors.lastname: Heinze
authors.forename: J
authors.initials: J
authors.lastname: Bertl
authors.forename: J
authors.initials: J
authors.lastname: Bauer
authors.forename: E K
authors.initials: EK
authors.lastname: Richfield
authors.forename: O
authors.initials: O
authors.lastname: Hornykiewicz
authors.forename: C
authors.initials: C
authors.lastname: Pifl
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002712:Chlorides / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017895:Manganese Compounds; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; D051844:alpha-Synuclein; C025340:manganese chloride; D004298:Dopamine