Mice Lacking α-Synuclein have an Attenuated Loss of Striatal Dopamine Following Prolonged Chronic MPTP Administration

• Published in: Neurotoxicology (Park Forest South) Vol. 25; no. 5; pp. 761 - 769
• Main Authors: Drolet, Robert E., Behrouz, Bahareh, Lookingland, Keith J., Goudreau, John L.
• Format: Journal Article
• Language: English
• Published: Orlando, FL Elsevier B.V 01.09.2004; Elsevier
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; 3,4-Dihydroxyphenylacetic Acid - metabolism; alpha-Synuclein; Animals; Biological and medical sciences; Blotting, Western; Dopamine; Dopamine - metabolism; Dopamine Agents - pharmacology; Dose-Response Relationship, Drug; Lactic Acid - metabolism; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; MPTP; Neostriatum - drug effects; Neostriatum - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neuropeptides; Parkinson’s disease; Substantia Nigra - metabolism; Synucleins; Toxicology; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins; α-Synuclein; α-Synuclein; Dopamine; MPTP; Parkinson’s disease; Nervous system diseases; Parkinson's disease; Acidic protein; Rodentia; Parkinson disease; α synuclein; Catecholamine; Cerebral disorder; Vertebrata; Chronic; Mammalia; Mouse; Animal; Dopamine agonist; Central nervous system disease; Neurotransmitter; Degenerative disease; Extrapyramidal syndrome; Prolonged
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2004.05.002

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.