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Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration.
Neurotoxicology. 2004 Sep; 25(5):761-9.N

Abstract

The functional role of alpha-synuclein in the pathogenesis of Parkinson's disease (PD) is not fully understood. Systemic exposure of alpha-synuclein-deficient mice to neurotoxins provides a direct approach to evaluate how alpha-synuclein may mediate cell death in a common murine model of PD. To this end, wild-type and homozygous alpha-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 alpha-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 alpha-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 alpha-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 alpha-synuclein. Despite attenuated toxicity, elevated lactate concentrations were observed in alpha-synuclein knock-out mice following prolonged, chronic MPTP administration. The results of this study provide evidence that alpha-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 alpha-synuclein expression.

Authors+Show Affiliations

The Neuroscience Program, Michigan State University, B-436 Life Sciences Building, East Lansing, MI 48824, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15288507

Citation

Drolet, Robert E., et al. "Mice Lacking Alpha-synuclein Have an Attenuated Loss of Striatal Dopamine Following Prolonged Chronic MPTP Administration." Neurotoxicology, vol. 25, no. 5, 2004, pp. 761-9.
Drolet RE, Behrouz B, Lookingland KJ, et al. Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology. 2004;25(5):761-9.
Drolet, R. E., Behrouz, B., Lookingland, K. J., & Goudreau, J. L. (2004). Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology, 25(5), 761-9.
Drolet RE, et al. Mice Lacking Alpha-synuclein Have an Attenuated Loss of Striatal Dopamine Following Prolonged Chronic MPTP Administration. Neurotoxicology. 2004;25(5):761-9. PubMed PMID: 15288507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. AU - Drolet,Robert E, AU - Behrouz,Bahareh, AU - Lookingland,Keith J, AU - Goudreau,John L, PY - 2003/12/06/received PY - 2004/05/06/accepted PY - 2004/8/4/pubmed PY - 2004/10/19/medline PY - 2004/8/4/entrez SP - 761 EP - 9 JF - Neurotoxicology JO - Neurotoxicology VL - 25 IS - 5 N2 - The functional role of alpha-synuclein in the pathogenesis of Parkinson's disease (PD) is not fully understood. Systemic exposure of alpha-synuclein-deficient mice to neurotoxins provides a direct approach to evaluate how alpha-synuclein may mediate cell death in a common murine model of PD. To this end, wild-type and homozygous alpha-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 alpha-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 alpha-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 alpha-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 alpha-synuclein. Despite attenuated toxicity, elevated lactate concentrations were observed in alpha-synuclein knock-out mice following prolonged, chronic MPTP administration. The results of this study provide evidence that alpha-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 alpha-synuclein expression. SN - 0161-813X UR - https://www.unboundmedicine.com/medline/citation/15288507/Mice_lacking_alpha_synuclein_have_an_attenuated_loss_of_striatal_dopamine_following_prolonged_chronic_MPTP_administration_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-813X(04)00072-5 DB - PRIME DP - Unbound Medicine ER -