Double-knockout mice for α- and β-synucleins: Effect on synaptic functions

doi:10.1073/pnas.0406283101

Double-knockout mice for α- and β-synucleins: Effect on synaptic functions

^*Center for Basic Neuroscience, Departments of ^∥Molecular Genetics, ^§Psychiatry, and ^¶Biochemistry, and ^**Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; ^†Department of Human Morphology and Applied Biology, University of Pisa and Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy; and ^‡Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461

Contributed by Thomas C. Südhof, September 2, 2004

Abstract

An abundant presynaptic protein, α-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of α-synuclein, possibly because α-synuclein is redundant with the very similar β-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack α- and/or β-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by ≈20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.

Footnotes

↵ †† To whom correspondence should be addressed. E-mail: thomas.sudhof{at}utsouthwestern.edu.
Author contributions: S.C., F.F., X.L., R.E.H., D.C.G., P.E.C., and T.C.S. designed research; S.C., F.F., H.-B.K., U.Y., D.A., R.E.H., X.L., G.B., D.C.G., and P.E.C. performed research; D.C.G., P.E.C., and T.C.S. analyzed data; S.C. and T.C.S. wrote the paper; and T.C.S. organized the funding, arranged the collaborations, and organized the regulatory approvals.
Abbreviations: GABA, γ-aminobutyric acid; KO, knockout; TH, tyrosine hydroxylase.