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

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. ORCID: https://orcid.org/0000-0002-7631-8352 and Chandra, Sreeganga S. 2010. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proceedings of the National Academy of Sciences of the United States of America 107 (45) , pp. 19573-19578. 10.1073/pnas.1005005107

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QH Natural history Q Science > QH Natural history > QH301 Biology R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords:	neurodegeneration; loss-of-function; Lewy bodies; ultrastructure; retina
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Last Modified:	19 Oct 2022 10:20
URI:	https://orca.cardiff.ac.uk/id/eprint/24055

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