Nudel Promotes Axonal Lysosome Clearance and Endo‐lysosome Formation via Dynein‐Mediated Transport
Nudel Promotes Axonal Lysosome Clearance and Endo‐lysosome Formation via Dynein‐Mediated Transport
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DOI：
10.1111/j.1600-0854.2009.00945.x
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发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Qiangge Zhang;Fubin Wang;Jingli Cao;Yidong Shen;Qiongping Huang;L. Bao;Xueliang Zhu
中科院分区：
文献类型：
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作者：
Qiangge Zhang;Fubin Wang;Jingli Cao;Yidong Shen;Qiongping Huang;L. Bao;Xueliang Zhu
轴突运输对神经元的功能和存活至关重要。细胞质动力蛋白及其附属复合体动力蛋白形成了一个微管，缺少负责逆行运输的末端定向马达。在这项研究中，我们发现，Nudel，动力蛋白调节，高表达的背根神经节（DRG）神经元。将抗Nudel抗体显微注射到培养的DRG神经元中，可消除轴突中膜性细胞器的逆行运输，并导致高尔基池分散在索马中。结果，通常富集在索马中的溶酶体持续地移动到轴突中，从而在轴突中积累。内溶酶体形成也明显延迟。由于线粒体的顺行运动没有受到抑制，抗体显然没有通过破坏轴突微管轨道来废除逆行运输。通过显微注射N末端Nudel、抗动力蛋白抗体或能够消除动力蛋白-动力蛋白结合的p150 Glued突变体获得了类似的结果。这些结果表明Nudel在动力蛋白介导的轴突运输中起关键作用。此外，动力蛋白对内溶酶体形成和溶酶体的区域隔离的影响可能有助于在具有动力蛋白功能障碍的患者或动物的神经元中观察到的内吞途径的缺陷。
Axonal transport is critical for neuronal function and survival. Cytoplasmic dynein and its accessory complex dynactin form a microtubule minus end‐directed motor in charge of retrograde transport. In this study, we show that Nudel, a dynein regulator, was highly expressed in dorsal root ganglion (DRG) neurons. Microinjection of anti‐Nudel antibody into cultured DRG neurons abolished retrograde transport of membranous organelles in the axon and led to dispersions of Golgi cisternae in the soma. As a result, lysosomes, which are normally enriched in the soma, moved persistently into and thus accumulated in axons. Endo‐lysosome formation was also markedly delayed. As anterograde motility of mitochondria was not inhibited, the antibody apparently did not abolish retrograde transport by destructing axonal microtubule tracks. Similar results were obtained by microinjecting N‐terminal Nudel, anti‐dynein antibody or a p150Glued mutant capable of abrogating the dynein–dynactin association. These results indicate a critical role of Nudel in dynein‐mediated axonal transport. Moreover, the effects of dynein on endolysosome formation and regional sequestration of lysosomes may contribute to defects in the endocytic pathway seen in neurons of patients or animals with malfunction of dynein.