Journal Article

ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity

Liu, Hao, Zhang, Yunlong, Waqas, Ahmed, Feng, Du, Zhang, Chuan, Zhuang, Haixia, Xu, Mindong, Umair, Muhammad, He, Zhengjie, Bai, Guo, Sun, Xiang-Dong, Chen, Xiaoting, Huang, Haofeng, Yan, Yousheng, Liu, Qian, Liu, Kunru, Lin, Shiyin, Meng, Tian, Huang, Huansen

2023

Overview

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). Atp9a null 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 the Atp9a null 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 14/19 / 14/32 / 14/35 / 42/89 / 631/378 / 631/80 / 64/60 / 82 / 82/1 / 82/29 / 82/80 / 82/83 / 9/74 / 96/109 / Animals / Attention Deficit Disorder with Hyperactivity - metabolism / Attention deficit hyperactivity disorder / Behavioral Sciences / Biological Psychology / Cortex (motor) / Cytology / Endosomes / Endosomes - metabolism / GTP-binding protein / Humans / Intellectual disabilities / Localization / Medicine / Medicine & Public Health / Mice / Morphology / Movement disorders / Muscle strength / Neurodevelopmental disorders / Neurological diseases / Neurosciences / Pharmacotherapy / Protein Transport / Protein turnover / Psychiatry / rab5 GTP-Binding Proteins - genetics / rab5 GTP-Binding Proteins - metabolism / Rab5 protein / Synaptic transmission