Behavioral defects in a DCTN1G71A transgenic mouse model of Perry syndrome
Behavioral defects in a DCTN1G71A transgenic mouse model of Perry syndrome
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DOI：
10.1016/j.neulet.2017.12.038
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发表时间：
2018-02-14
影响因子：
2.5
通讯作者：
Tsuboi, Yoshio
中科院分区：
文献类型：
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作者：
Mishima, Takayasu;Deshimaru, Manami;Tsuboi, Yoshio
佩里综合征是一种罕见的神经退行性疾病，以帕金森、抑郁/冷漠、体重减轻和中枢性低通气为特征。我们之前进行的全基因组关联扫描和随后的研究在Perry综合征患者中发现了DCTN1的9个突变，DCTN1是dynactin复合体的最大蛋白质亚基。其中包括p150（glue）微管结合细胞骨架相关蛋白Gly-rich结构域中的G71A。动力蛋白复合物是微管为基础的细胞质逆行运动动力蛋白的功能所必需的。为了验证DCTN1基因G71A突变足以引起Perry综合征的假设，我们培育了DCTN1（G71A）转基因小鼠。这些小鼠最初发育正常，但幼年动物的探索活动减少，老年动物的运动协调能力受损。这些行为缺陷类似于佩里综合征中出现的冷漠样症状和帕金森病。尽管TDP-43的病理聚集被认为是Perry综合征的主要神经病理特征，但在转基因小鼠的黑质和大脑皮层中未检测到TDP-43聚集物。我们的研究表明，DCTN1基因的单一突变再现了Perry综合征患者的症状，并提供证据表明DCTN1（G71A）转基因小鼠代表了一种新的Perry综合征啮齿动物模型。
Perry syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously-conducted genome-wide association scan and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150(Glued). The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein.To test the hypothesis that the G71A mutation in the DCTN1 gene is sufficient to cause Perry syndrome, we generated DCTN1(G71A) transgenic mice. These mice initially developed normally, but young animals showed decreased exploratory activity and aged animals showed impaired motor coordination. These behavioral defects parallel apathy-like symptoms and parkinsonism encountered in Perry syndrome. TDP-43 aggregates were not detected in the substantia nigra and cerebral cortex of the transgenic mice, although pathological aggregates of TDP-43 have been considered a major neuropathological feature of Perry syndrome. Our study reveals that a single mutation in the DCTN1 gene recapitulates symptoms of Perry syndrome patients, and provides evidence that DCTN1(G71A) transgenic mice represent a novel rodent model of Perry syndrome.