Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration.
Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration.
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DOI：
10.1523/jneurosci.3985-08.2009
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发表时间：
2009-01-07
期刊：
影响因子：
--
通讯作者：
Schubert D
中科院分区：
文献类型：
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作者：
Chen Q;Peto CA;Shelton GD;Mizisin A;Sawchenko PE;Schubert D
轴突功能障碍是许多神经退行性疾病的主要表型变化，但其背后的过程尚不清楚。细胞粘附修饰因子（Modifier of cell adhesion， MOCA）是一种早老素结合蛋白，作为Rac1的鸟嘌呤核苷酸交换因子。小鼠MOCA缺失导致轴突变性，并通过降低cofilin磷酸化和改变其上游信号伙伴LIM激酶和p21活化激酶（一种直接位于Rac1下游的酶）而导致感觉运动障碍。在moca缺陷小鼠中发现的轴突营养不良与神经丝蛋白的异常聚集、轴突细胞骨架的紊乱以及自噬液泡和多泛素化蛋白的积累有关。此外，MOCA缺乏导致肌动蛋白细胞骨架的改变和含有cofilin的棒状结构的形成。营养不良的轴突表现出功能异常，包括轴突运输受损。这些发现表明，MOCA是维持轴突功能完整性所必需的，并为导致轴突退化的步骤定义了一个模型。
Axonal dysfunction is the major phenotypic change in many neurodegenerative diseases, but the processes underlying this impairment are not clear. Modifier of cell adhesion (MOCA) is a presenilin binding protein that functions as a guanine nucleotide exchange factor for Rac1. The loss of MOCA in mice leads to axonal degeneration and causes sensorimotor impairments by decreasing cofilin phosphorylation and altering its upstream signaling partners LIM kinase and p21-activated kinase, an enzyme directly downstream of Rac1. The dystrophic axons found in MOCA-deficient mice are associated with abnormal aggregates of neurofilament protein, the disorganization of the axonal cytoskeleton, and the accumulation of autophagic vacuoles and polyubiquitinated proteins. Furthermore, MOCA deficiency causes an alteration in the actin cytoskeleton and the formation of cofilin-containing rod-like structures. The dystrophic axons show functional abnormalities, including impaired axonal transport. These findings demonstrate that MOCA is required for maintaining the functional integrity of axons and define a model for the steps leading to axonal degeneration.