Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration

ATP6AP2 is an essential accessory component of the vacuolar H+ ATPase (V-ATPase) and has been associated with intellectual disabilities (ID) and Parkinsonism. ATP6AP2 has been implicated in several signaling pathways, but little is known about its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional ATP6AP2 Drosophila and mouse models in the nervous system. In Drosophila, knockdown of ATP6AP2 induced defective phototaxis and vacuolisation of photoreceptor neurons and pigment cells when deleted in eyes and alteration of short- and long-term memory when deleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2Camk2aCre/0 mice) caused increased spontaneous locomotor activity and altered memory for fear. Both Drosophila ATP6AP2 knockdown and Atp6ap2Camk2aCre/0 mice presented with presynaptic transmission defect, abnormal number and morphology of synapses, and alteration of axonal transport in fly. In addition, Atp6ap2Camk2aCre/0 mice showed autophagy defect leading to axonal and neuronal degeneration in the cortex and the hippocampus. Surprisingly, myelinisation of axons was affected in our mutant mice. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2Camk2aCre/0 mouse hippocampi revealed dysregulated genes involved in myelination, action potential, membrane bound vesicles and adult behaviour. In summary, disruption of ATP6AP2 in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system. 4 samples, 2 wt and 2 Atp6ap2Camk2aCre/0ATP6AP2是液泡型H+-ATP酶（V-ATPase）的必需辅助组分，且与智力障碍（ID）及帕金森综合征相关。ATP6AP2已被证实参与多条信号通路，但目前对其在神经系统中的功能尚不清楚。为阐明其在行为与认知中的作用，我们构建并鉴定了神经系统中条件性敲除ATP6AP2的果蝇与小鼠模型。在果蝇中，于眼部敲低ATP6AP2可诱导感光神经元及色素细胞出现趋光行为缺陷与空泡化；于蘑菇体中敲除ATP6AP2则会导致短期与长期记忆受损。在小鼠中，于谷氨酸能神经元中条件性敲除Atp6ap2（即Atp6ap2Camk2aCre/0小鼠）可引发自发运动活性升高与恐惧记忆异常。果蝇ATP6AP2敲低模型与Atp6ap2Camk2aCre/0小鼠均表现出突触前传递缺陷、突触数量与形态异常，且果蝇中存在轴突运输紊乱。此外，Atp6ap2Camk2aCre/0小鼠存在自噬缺陷，进而导致皮层与海马体中的轴突及神经元变性。值得注意的是，突变小鼠的轴突髓鞘形成亦受到影响。与跨物种鉴定到的表型一致，对Atp6ap2Camk2aCre/0小鼠海马体进行全基因组转录组分析发现，与髓鞘形成、动作电位、膜结合囊泡及成年行为相关的基因表达失调。综上，在小鼠与果蝇中敲除ATP6AP2均可导致认知障碍与神经变性，模拟了人类ATP6AP2突变相关神经病理的部分特征。本研究证实ATP6AP2是神经系统的必需基因。本研究共纳入4份样本，其中2份为野生型（WT），2份为Atp6ap2Camk2aCre/0小鼠。