Ke Yuting, Weng Meiqian, Chhetri Gaurav, Usman Muhammad, Li Yan, Yu Qing, Ding Yingzhuo, Wang Zejian, Wang Xiaolong, Sultana Pinky, DiFiglia Marian, Li Xueyi
School of Pharmacy, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Sci Adv. 2020 Nov 18;6(47). doi: 10.1126/sciadv.abb7781. Print 2020 Nov.
Genetic mutations in the gene encoding transport protein particle complex 9 (trappc9), a subunit of TRAPP that acts as a guanine nucleotide exchange factor for rab proteins, cause intellectual disability with brain structural malformations by elusive mechanisms. Here, we report that trappc9-deficient mice exhibit a broad range of behavioral deficits and postnatal delay in growth of the brain. Contrary to volume decline of various brain structures, the striatum of trappc9 null mice was enlarged. An imbalance existed between dopamine D1 and D2 receptor containing neurons in the brain of trappc9-deficient mice; pharmacological manipulation of dopamine receptors improved performances of trappc9 null mice to levels of wild-type mice on cognitive tasks. Loss of trappc9 compromised the activation of rab11 in the brain and resulted in retardation of endocytic receptor recycling in neurons. Our study elicits a pathogenic mechanism and a potential treatment for trappc9-linked disorders including intellectual disability.
编码转运蛋白颗粒复合物9（TRAPPC9）的基因突变会导致智力残疾并伴有脑结构畸形，其机制尚不清楚。TRAPPC9是TRAPP的一个亚基，作为rab蛋白的鸟嘌呤核苷酸交换因子发挥作用。在此，我们报告TRAPPC9缺陷小鼠表现出广泛的行为缺陷和出生后脑生长延迟。与各种脑结构体积减小相反，TRAPPC9基因敲除小鼠的纹状体增大。TRAPPC9缺陷小鼠大脑中含多巴胺D1和D2受体的神经元之间存在失衡；对多巴胺受体进行药理学操作可将TRAPPC9基因敲除小鼠在认知任务中的表现提高到野生型小鼠的水平。TRAPPC9的缺失损害了大脑中rab11的激活，并导致神经元内吞受体再循环延迟。我们的研究揭示了一种致病机制以及针对包括智力残疾在内的TRAPPC9相关疾病的潜在治疗方法。
