αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 45; pp. 19573 - 19578
• Main Authors: Greten-Harrison, Becket, Polydoro, Manuela, Morimoto-Tomita, Megumi, Diao, Ling, Williams, Andrew M, Nie, Esther H, Makani, Sachin, Tian, Ning, Castillo, Pablo E, Buchman, Vladimir L, Chandra, Sreeganga S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.11.2010; National Acad Sciences
• Subjects: Age Factors; alpha-Synuclein - deficiency; alpha-Synuclein - genetics; Animals; beta-Synuclein - deficiency; beta-Synuclein - genetics; Biological Sciences; Brain; Computer mice; gamma-Synuclein - deficiency; gamma-Synuclein - genetics; Gene Deletion; Hippocampus; Input output; Mice; Mice, Knockout; Nerve Tissue Proteins - analysis; Neurons; Neurons - physiology; Neuroscience; Parkinson disease; Parkinson Disease - etiology; Phenotype; Synapses; Synapses - pathology; Synaptic Transmission - genetics; Synucleins; Synucleins - deficiency; Synucleins - genetics; Synucleins - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1005005107

Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, α-, β-, and γ-synuclein. α-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized αβγ-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by ~30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease.