PDF(Pubmed)
Abstract：
Homotypic Fusion and Protein Sorting (HOPS) and Class C-core Vacuole/Endosome Tethering (CORVET) complexes regulate the correct fusion of endolysosomal bodies. Mutations in core proteins (VPS11, VPS16, VPS18, and VPS33) have been linked with multiple neurological disorders, including mucopolysaccharidosis (MPS), genetic leukoencephalopathy (gLE), and dystonia. Mutations in human Vacuolar Protein Sorting 16 (VPS16) have been associated with MPS and dystonia. In this study, we generated and characterized a zebrafish vps16(-/-) mutant line using immunohistochemical and behavioral approaches. The loss of Vps16 function caused multiple systemic defects, hypomyelination, and increased neuronal cell death. Behavioral analysis showed a progressive loss of visuomotor response and reduced motor response and habituation to acoustic/tap stimuli in mutants. Finally, using a novel multiple-round acoustic/tap stimuli test, mutants showed intermediate memory deficits. Together, these data demonstrate that zebrafish vps16(-/-) mutants show systemic defects, neurological and motor system pathologies, and cognitive impairment. This is the first study to report behavior abnormalities and memory deficiencies in a zebrafish vps16(-/-) mutant line. Finally, we conclude that the deficits observed in vps16(-/-) zebrafish mutants do not mimic pathologies associated with dystonia, but more align to abnormalities associated with MPS and gLE.
摘要：
同型融合和蛋白质分选（HOPS）和C类核心液泡/内体系链（CORVET）复合物调节内溶酶体体的正确融合。核心蛋白（VPS11，VPS16，VPS18和VPS33）的突变与多种神经系统疾病有关，包括粘多糖贮积症（MPS），遗传性白质脑病（gLE），和肌张力障碍.人液泡蛋白分选16（VPS16）的突变与MPS和肌张力障碍有关。在这项研究中,我们使用免疫组织化学和行为方法生成并表征了斑马鱼vps16（-/-）突变系。Vps16功能的丧失导致多个系统缺陷，髓鞘减少,和增加神经元细胞死亡。行为分析表明，突变体的视觉运动反应逐渐丧失，运动反应和对声学/轻敲刺激的习惯降低。最后,使用新颖的多轮声学/敲击刺激测试，突变体表现出中间记忆缺陷。一起,这些数据表明斑马鱼vps16（-/-）突变体显示出系统缺陷，神经和运动系统病理学，和认知障碍。这是第一项报告斑马鱼vps16（-/-）突变品系行为异常和记忆缺陷的研究。最后,我们得出的结论是，在vps16（-/-）斑马鱼突变体中观察到的缺陷并不模拟与肌张力障碍相关的病理，但更多的是与MPS和gLE相关的异常。
