Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.
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.
Center for Basic Neuroscience, Department of Molecular Genetics, and The Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. oliver.schluter@stanford.edu
O M
OM
Schlüter
F
F
Fornai
M G
MG
Alessandrí
S
S
Takamori
M
M
Geppert
R
R
Jahn
T C
TC
Südhof
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001757:Blastomeres / Q000378:metabolism; D015139:Blotting, Southern / Q000379:methods; D003342:Corpus Striatum / Q000378:metabolism; D017931:DNA Primers / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D020267:MPTP Poisoning; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D051843:Synucleins; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein
D018759:Adrenergic Uptake Inhibitors; D000906:Antibodies; D017931:DNA Primers; D018765:Dopamine Uptake Inhibitors; D009419:Nerve Tissue Proteins; D010879:Piperazines; C497604:SNCA protein, human; C497605:Snca protein, mouse; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D018698:Glutamic Acid; D008694:Methamphetamine; D012110:Reserpine; C043425:vanoxerine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid