αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction.
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.
Greten-Harrison
Becket
B
Program in Cellular Neuroscience, Neurodegeneration, and Repair and Department of Neurology, Yale University, New Haven, CT 06536, USA.
Polydoro
Manuela
M
Morimoto-Tomita
Megumi
M
Diao
Ling
L
Williams
Andrew M
AM
Nie
Esther H
EH
Makani
Sachin
S
Tian
Ning
N
Castillo
Pablo E
PE
Buchman
Vladimir L
VL
Chandra
Sreeganga S
SS
D000367:Age Factors; D000818:Animals; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000502:physiology*; D010300:Parkinson Disease / Q000209:etiology; D010641:Phenotype; D013569:Synapses / Q000473:pathology*; D009435:Synaptic Transmission / Q000235:genetics*; D051843:Synucleins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D051844:alpha-Synuclein / Q000172:deficiency / Q000235:genetics; D051846:beta-Synuclein / Q000172:deficiency / Q000235:genetics; D051845:gamma-Synuclein / Q000172:deficiency / Q000235:genetics
D009419:Nerve Tissue Proteins; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein