ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity.
ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity.
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ATP9A 缺陷通过调节 RAB5 和 RAB11 活性导致 ADHD 和异常内体循环
DOI：
10.1038/s41380-022-01940-w
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发表时间：
2023-03
影响因子：
11
通讯作者：
Feng, Du
中科院分区：
文献类型：
--
作者：
Meng, Tian;Chen, Xiaoting;He, Zhengjie;Huang, Haofeng;Lin, Shiyin;Liu, Kunru;Bai, Guo;Liu, Hao;Xu, Mindong;Zhuang, Haixia;Zhang, Yunlong;Waqas, Ahmed;Liu, Qian;Zhang, Chuan;Sun, Xiang-Dong;Huang, Huansen;Umair, Muhammad;Yan, Yousheng;Feng, Du
ATP 9A是一种Ⅱ类P4-ATP酶的脂质翻转酶，参与细胞囊泡运输。它的纯合变体与人类神经发育障碍有关。然而，其生理功能，潜在的机制以及其在人类和动物中的病理生理学相关性仍然在很大程度上未知。在这里，我们报告了两个独立的家族，其中无义突变c.433C>T/c.658C>T/c.983G>A（p.Arg145 */p.Arg220 */p.Trp328 *）（NM_006045.3）引起常染色体隐性张力减退、智力残疾（ID）和注意力缺陷多动障碍（ADHD）。Atp 9anull小鼠显示肌肉力量降低，记忆缺陷和多动性运动障碍，概括了在患者中观察到的症状。在Atp 9anull小鼠的初级运动皮层和海马中发现异常的神经突形态和受损的突触传递。ATP 9A也是维持神经元轴突形态和体外神经细胞活力所必需的。它主要定位于内体，并通过调节小GTPase RAB 5和RAB 11的激活在内体回收途径中发挥关键作用。然而，ATP 9A致病突变体具有异常的亚细胞定位并引起异常的内体再循环。这些发现提供了强有力的证据，表明ATP 9A缺陷导致人类和小鼠的神经发育障碍和突触功能障碍，并建立了ATP 9A在RAB 5和RAB 11活性依赖性内体再循环途径和神经系统疾病中的新的调节作用。
ATP9A, a lipid flippase of the class II P4-ATPases, is involved in cellular vesicle trafficking. Its homozygous variants are linked to neurodevelopmental disorders in humans. However, its physiological function, the underlying mechanism as well as its pathophysiological relevance in humans and animals are still largely unknown. Here, we report two independent families in which the nonsense mutations c.433C>T/c.658C>T/c.983G>A (p. Arg145*/p. Arg220*/p. Trp328*) in ATP9A (NM_006045.3) cause autosomal recessive hypotonia, intellectual disability (ID) and attention deficit hyperactivity disorder (ADHD).Atp9anull mice show decreased muscle strength, memory deficits and hyperkinetic movement disorder, recapitulating the symptoms observed in patients. Abnormal neurite morphology and impaired synaptic transmission are found in the primary motor cortex and hippocampus of theAtp9anull mice. ATP9A is also required for maintaining neuronal neurite morphology and the viability of neural cells in vitro. It mainly localizes to endosomes and plays a pivotal role in endosomal recycling pathway by modulating small GTPase RAB5 and RAB11 activation. However, ATP9A pathogenic mutants have aberrant subcellular localization and cause abnormal endosomal recycling. These findings provide strong evidence that ATP9A deficiency leads to neurodevelopmental disorders and synaptic dysfunctions in both humans and mice, and establishes novel regulatory roles for ATP9A in RAB5 and RAB11 activity-dependent endosomal recycling pathway and neurological diseases.
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ATP11C靶向小鼠中央肝细胞中的基底外侧胆汁盐转运蛋白。
DOI：
10.1002/hep.28522
发表时间：
2016-07
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
de Waart DR;Naik J;Utsunomiya KS;Duijst S;Ho-Mok K;Bolier AR;Hiralall J;Bull LN;Bosma PJ;Oude Elferink RP;Paulusma CC
通讯作者：
Paulusma CC
影响因子：
5.3
作者：
Franke B;Neale BM;Faraone SV
通讯作者：
Faraone SV
影响因子：
4.7
作者：
Levano K;Punia V;Raghunath M;Debata PR;Curcio GM;Mogha A;Purkayastha S;McCloskey D;Fata J;Banerjee P
通讯作者：
Banerjee P
影响因子：
5.1
作者：
Chandran, Jayanth;Ding, Jinhui;Cai, Huaibin
通讯作者：
Cai, Huaibin
DOI：
10.1016/j.bbadis.2016.06.005
发表时间：
2016-09-01
影响因子：
6.2
作者：
Kerr, Daniel J.;Marsillo, Alexandra;Banerjee, Probal
通讯作者：
Banerjee, Probal