Role of α-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice

• Published in: Neuroscience Vol. 118; no. 4; pp. 985 - 1002
• Main Authors: SCHLÜTER, O. M, FORNAI, F, ALESSANDRI, M. G, TAKAMORI, S, GEPPERT, M, JAHN, R, SÜDHOF, T. C
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.06.2003
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Adrenergic Uptake Inhibitors - pharmacology; alpha-Synuclein; Animals; Antibodies - metabolism; Biological and medical sciences; Blastomeres - metabolism; Blotting, Southern - methods; Corpus Striatum - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; DNA Primers - metabolism; Dopamine - metabolism; Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Glutamic Acid - metabolism; Hippocampus - metabolism; Homovanillic Acid - metabolism; Humans; Immunoblotting - methods; Immunohistochemistry - methods; Medical sciences; Methamphetamine - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout - genetics; Mice, Knockout - metabolism; Mice, Transgenic; MPTP Poisoning; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons - metabolism; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - metabolism; Piperazines - pharmacology; Rats; Reserpine - pharmacology; Serotonin - metabolism; Stem Cells - metabolism; Subcellular Fractions - metabolism; Substantia Nigra - metabolism; Synucleins; Tyrosine 3-Monooxygenase - metabolism; Animal model; Nervous system diseases; Dopamine; Rodentia; Parkinson disease; Synaptic vesicle; synapse; Catecholamine; Synuclein; neurotransmitter release; Cerebral disorder; Vertebrata; Mammalia; Mouse; methamphetamine; Central nervous system disease; Neurotransmitter; Degenerative disease; Release; Extrapyramidal syndrome
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(03)00036-8

In humans, mutations in the alpha-synuclein gene or exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produce Parkinson's disease with loss of dopaminergic neurons and depletion of nigrostriatal dopamine. alpha-Synuclein is a vertebrate-specific component of presynaptic nerve terminals that may function in modulating synaptic transmission. To test whether MPTP toxicity involves alpha-synuclein, we generated alpha-synuclein-deficient mice by homologous recombination, and analyzed the effect of deleting alpha-synuclein on MPTP toxicity using these knockout mice. In addition, we examined commercially available mice that contain a spontaneous loss of the alpha-synuclein gene. As described previously, deletion of alpha-synuclein had no significant effects on brain structure or composition. In particular, the levels of synaptic proteins were not altered, and the concentrations of dopamine, dopamine metabolites, and dopaminergic proteins were unchanged. Upon acute MPTP challenge, alpha-synuclein knockout mice were partly protected from chronic depletion of nigrostriatal dopamine when compared with littermates of the same genetic background, whereas mice carrying the spontaneous deletion of the alpha-synuclein gene exhibited no protection. Furthermore, alpha-synuclein knockout mice but not the mice with the alpha-synuclein gene deletion were slightly more sensitive to methamphetamine than littermate control mice. These results demonstrate that alpha-synuclein is not obligatorily coupled to MPTP sensitivity, but can influence MPTP toxicity on some genetic backgrounds, and illustrate the need for extensive controls in studies aimed at describing the effects of mouse knockouts on MPTP sensitivity.