TY - JOUR
T1 - αβγ-Synuclein triple knockout mice revealage-dependent neuronal dysfunction
AU - Greten-Harrison, Becket
AU - Polydoro, Manuela
AU - Morimoto-Tomita, Megumi
AU - Diao, Ling
AU - Williams, Andrew M.
AU - Nie, Esther H.
AU - Makani, Sachin
AU - Tian, Ning
AU - Castillo, Pablo E.
AU - Buchman, Vladimir L.
AU - Chandra, Sreeganga S.
PY - 2010/11/9
Y1 - 2010/11/9
N2 - 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.
AB - 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.
KW - Lewy bodies
KW - Loss-of-function
KW - Neurodegeneration
KW - Retina
KW - Ultrastructure
UR - http://www.scopus.com/inward/record.url?scp=78650431984&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650431984&partnerID=8YFLogxK
U2 - 10.1073/pnas.1005005107
DO - 10.1073/pnas.1005005107
M3 - Article
C2 - 20974939
AN - SCOPUS:78650431984
SN - 0027-8424
VL - 107
SP - 19573
EP - 19578
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -