Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.
Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.
复制标题
DOI：
10.1093/hmg/ddv380
复制
发表时间：
2015-12-01
影响因子：
3.5
通讯作者：
Herault Y
中科院分区：
文献类型：
--
作者：
Dubos A;Castells-Nobau A;Meziane H;Oortveld MA;Houbaert X;Iacono G;Martin C;Mittelhaeuser C;Lalanne V;Kramer JM;Bhukel A;Quentin C;Slabbert J;Verstreken P;Sigrist SJ;Messaddeq N;Birling MC;Selloum M;Stunnenberg HG;Humeau Y;Schenck A;Herault Y
ATP 6AP 2是液泡H+ ATP酶（V-ATP酶）的重要辅助成分，与智力残疾（ID）和帕金森综合征有关。ATP 6AP 2参与了几种信号通路;然而，关于其在神经系统中的作用知之甚少。为了解释其在行为和认知中的功能，我们在果蝇和小鼠模型的神经系统中产生并表征了ATP 6AP 2的条件性敲除。在果蝇中，ATP 6AP 2敲低诱导缺陷趋光性和空泡化的感光神经元和色素细胞时，耗尽的眼睛和改变短期和长期记忆时，耗尽的蘑菇体。在小鼠中，条件性Atp 6ap 2缺失的海马能神经元（Atp 6ap 2Camk 2aCre/0小鼠）引起增加的自发活动和改变的恐惧记忆。果蝇ATP 6AP 2基因敲除小鼠和Atp 6ap 2Camk 2aCre/0小鼠均表现出突触前传递缺陷，突触数量和形态异常。此外，Atp 6ap 2Camk 2aCre/0小鼠表现出自噬缺陷，导致皮质和海马中的轴突和神经元变性。令人惊讶的是，我们的突变小鼠的轴突髓鞘形成受到影响，并在果蝇中观察到轴突运输的改变。根据跨物种鉴定的表型，Atp 6ap 2Camk 2aCre/0小鼠腹侧肌的全基因组转录组分析揭示了参与髓鞘形成、动作电位、膜结合囊泡和运动行为的基因的失调。总之，小鼠和苍蝇中的ATP 6AP 2破坏导致认知障碍和神经变性，模拟了与人类中ATP 6AP 2突变相关的神经病理学的方面。我们的研究结果确定ATP 6AP 2作为神经系统的必需基因。
ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2Camk2aCre/0 mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2Camk2aCre/0 mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2Camk2aCre/0 mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2Camk2aCre/0 mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption 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.