Mice Lacking α-Synuclein have an Attenuated Loss of Striatal Dopamine Following Prolonged Chronic MPTP Administration
The functional role of α-synuclein in the pathogenesis of Parkinson’s disease (PD) is not fully understood. Systemic exposure of α-synuclein-deficient mice to neurotoxins provides a direct approach to evaluate how α-synuclein may mediate cell death in a common murine model of PD. To this end, wild-t...
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Published in | Neurotoxicology (Park Forest South) Vol. 25; no. 5; pp. 761 - 769 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Orlando, FL
Elsevier B.V
01.09.2004
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | The functional role of α-synuclein in the pathogenesis of Parkinson’s disease (PD) is not fully understood. Systemic exposure of α-synuclein-deficient mice to neurotoxins provides a direct approach to evaluate how α-synuclein may mediate cell death in a common murine model of PD. To this end, wild-type and homozygous α-synuclein knock-out mice were treated with sub-chronic and prolonged, chronic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the sub-chronic model, wild-type and α-synuclein knock-out mice were treated for five consecutive days with MPTP (1–25
mg/kg, s.c.) or vehicle, and sacrificed 3 days following the last injection. The prolonged, chronic model consisted of two injections of MPTP (1–20
mg/kg, s.c.) per week for 5 weeks, with co-administration of probenecid (250
mg/kg, i.p.), and animals were sacrificed 3 weeks following the last injection. Sub-chronic administration of MPTP caused a dramatic, dose-dependent decrease in striatal dopamine (DA) concentrations, while an attenuated response was observed in α-synuclein knock-out mice. Similarly, prolonged, chronic administration of MPTP produced a dose-dependent decrease in striatal DA concentrations, and a corresponding loss of striatal vesicular monoamine transporter (VMAT-2) protein in wild-type mice. However, mice lacking α-synuclein had an attenuated loss of striatal DA concentrations, while no loss of striatal VMAT-2 protein was observed. Both sub-chronic and prolonged, chronic administration of MPTP caused an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC) to DA ratio in wild-type mice, but not in mice lacking α-synuclein. Despite attenuated toxicity, elevated lactate concentrations were observed in α-synuclein knock-out mice following prolonged, chronic MPTP administration. The results of this study provide evidence that α-synuclein null mice have an attenuated response to the toxic effects of MPTP exposure, even over prolonged periods of time and that the biochemical sequela of a protracted insult to nigrostriatal DA neurons are distinct between mice with and without α-synuclein expression. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0161-813X 1872-9711 |
DOI: | 10.1016/j.neuro.2004.05.002 |