Leshchyns'ka Iryna, Sytnyk Vladimir, Richter Melanie, Andreyeva Aksana, Puchkov Dmytro, Schachner Melitta
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
Neuron. 2006 Dec 21;52(6):1011-25. doi: 10.1016/j.neuron.2006.10.020.
In searching for binding partners of the intracellular domain of the immunoglobulin superfamily adhesion molecule CHL1, we identified the clathrin-uncoating ATPase Hsc70. CHL1 gene ablation resulted in reduced targeting of Hsc70 to the synaptic plasma membrane and synaptic vesicles, suggesting CHL1 as a synapse-targeting cue for Hsc70. CHL1 accumulates in presynaptic membranes and, in response to synapse activation, is targeted to synaptic vesicles by endocytosis. CHL1 deficiency or disruption of the CHL1/Hsc70 complex results in accumulation of abnormally high levels of clathrin-coated synaptic vesicles with a reduced ability to release clathrin. Generation of new clathrin-coated synaptic vesicles in an activity-dependent manner is inhibited when the CHL1/Hsc70 complex is disrupted, resulting in impaired uptake and release of FM dyes in synaptic boutons. Abnormalities in clathrin-dependent synaptic vesicle recycling may thus underlie brain malfunctions in humans and mice that carry mutations in the CHL1 gene.
在寻找免疫球蛋白超家族粘附分子CHL1细胞内结构域的结合伴侣时，我们鉴定出了网格蛋白脱衣被ATP酶Hsc70。CHL1基因敲除导致Hsc70靶向突触质膜和突触小泡的能力降低，这表明CHL1是Hsc70的突触靶向线索。CHL1在突触前膜中积累，并且在突触激活时，通过内吞作用靶向突触小泡。CHL1缺陷或CHL1/Hsc70复合物的破坏会导致异常高水平的网格蛋白包被突触小泡积累，且释放网格蛋白的能力降低。当CHL1/Hsc70复合物被破坏时，以活性依赖方式生成新的网格蛋白包被突触小泡受到抑制，导致突触小体中FM染料的摄取和释放受损。因此，网格蛋白依赖性突触小泡循环异常可能是携带CHL1基因突变的人类和小鼠脑功能障碍的基础。
