Synaptic vesicle recycling is enhanced by torsinA that harbors the DYT1 dystonia mutation.
Early-onset generalized dystonia, DYT1, is caused by a mutation in the gene encoding the evolutionarily conserved AAA+ ATPase torsinA. Synaptic abnormalities have been implicated in DYT1 dystonia, but the details of the synaptic pathophysiology are only partially understood. Here, we demonstrate a novel role for torsinA in synaptic vesicle recycling, using cultured hippocampal neurons from a knock-in mouse model of DYT1 dystonia (ΔE-torsinA) and live-cell imaging with styryl FM dyes. Neurons from heterozygous ΔE-torsinA mice released a larger fraction of the total recycling pool (TRP) during a single round of electrical stimulation than did wild-type neurons. Moreover, when the neurons were subjected to prior high activity, the time course of release was shortened. In neurons from homozygous mice, these enhanced exocytosis phenotypes were similar, but in addition the size of the TRP was reduced. Notably, when release was triggered by applying a calcium ionophore rather than electrical stimuli, neither a single nor two ΔE-torsinA alleles affected the time course of release. Thus, the site of action of ΔE-torsinA is at or upstream of the rise in calcium concentration in nerve terminals. Our results suggest that torsinA regulates synaptic vesicle recycling in central neurons. They also indicate that this regulation is influenced by neuronal activity, further supporting the idea that synaptic abnormalities contribute to the pathophysiology of DYT1 dystonia.
Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Yasuhiro
Y
Kakazu
Jin-Young
JY
Koh
K W David
KW
Ho
Pedro
P
Gonzalez-Alegre
N Charles
NC
Harata
D000818:Animals; D002478:Cells, Cultured; D020821:Dystonic Disorders / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D051379:Mice; D023421:Models, Animal; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*
C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones