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.
Program in Cellular Neuroscience, Neurodegeneration, and Repair and Department of Neurology, Yale University, New Haven, CT 06536, USA.
Becket
B
Greten-Harrison
Manuela
M
Polydoro
Megumi
M
Morimoto-Tomita
Ling
L
Diao
Andrew M
AM
Williams
Esther H
EH
Nie
Sachin
S
Makani
Ning
N
Tian
Pablo E
PE
Castillo
Vladimir L
VL
Buchman
Sreeganga S
SS
Chandra
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