αβγ-Synuclein triple knockout mice revealage-dependent neuronal dysfunction

Becket Greten-Harrison, Manuela Polydoro, Megumi Morimoto-Tomita, Ling Diao, Andrew M. Williams, Esther H. Nie, Sachin Makani, Ning Tian, Pablo E. Castillo, Vladimir L. Buchman, Sreeganga S. Chandra

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)19573-19578
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number45
DOIs
StatePublished - Nov 9 2010

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Keywords

  • Lewy bodies
  • Loss-of-function
  • Neurodegeneration
  • Retina
  • Ultrastructure

ASJC Scopus subject areas

  • General

Cite this

Greten-Harrison, B., Polydoro, M., Morimoto-Tomita, M., Diao, L., Williams, A. M., Nie, E. H., Makani, S., Tian, N., Castillo, P. E., Buchman, V. L., & Chandra, S. S. (2010). αβγ-Synuclein triple knockout mice revealage-dependent neuronal dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 107(45), 19573-19578. https://doi.org/10.1073/pnas.1005005107