Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration.
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.
The Neuroscience Program, Michigan State University, B-436 Life Sciences Building, East Lansing, MI 48824, USA.
Robert E
RE
Drolet
Bahareh
B
Behrouz
Keith J
KJ
Lookingland
John L
JL
Goudreau
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019344:Lactic Acid / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides; D013378:Substantia Nigra / Q000378:metabolism; D051843:Synucleins; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein
D015259:Dopamine Agents; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C497605:Snca protein, mouse; D051843:Synucleins; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; D019344:Lactic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine