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. Overall design: 4 samples, 2 wt and 2 Atp6ap2Camk2aCre/0

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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