ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR195/000/SRR1951440/SRR1951440.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR195/001/SRR1951441/SRR1951441.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR195/002/SRR1951442/SRR1951442.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR195/009/SRR1951439/SRR1951439.fastq.gzprimaryOK200GenomicsMultiomicsHolger Heyn, single cell sequencing, CNAG,Centro Nacional de Análisis Genómicohttps://www.ebi.ac.uk/ena/browser/view/PRJNA280215Mus musculusxref:PubMed:26376863ATP6AP2 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/0ENAMental, Juvenile Parkinson Disease, Autosomal Recessive, Disorders, Materials, Impairment, ATP6M8-9, Laboratory, Early Onset, MENTAL DEFIC, Mus domesticus, Intellectual Disabilities, Deficiencies, Mild, Poor school performance, RENR, Cognitive Dysfunctions, Gene, Chromosome 6 Linked Autosomal Recessive Parkinsonism, Parkinsonian Diseases, Deteriorations, Dysfunctions, House Mouse, With Diurnal Fluctuation, Cognitive Declines, House, Mus musculus domesticus, Autosomal Recessive Juvenile, Mice, Autosomal Dominant Juvenile Parkinsonism, intellectual disability, Familial Juvenile Parkinsonism, Intellectual impairment, Retardation, ELDF10, Mental Retardation, Genetic, Disabilities, Swiss, Cognitive deficits, Low intelligence, Dull intelligence, M8-9, Cognitive Disorders, Swiss Mice, Intellectual, Familial, (P)RR, Atp6ip2, APT6M8-9, Cognitive defects, Familial Parkinson Disease, Ramsay Hunt Paralysis Syndrome, Dominant Parkinsonism, Disorder, Parkinson Disease, Parkinsonism, Experimental Parkinsonism, MPTP-Induced, Deterioration, Retardations, MRXE, house mouse, 5730403E06Rik, Cognitive Disorder, Parkinson Disease Autosomal Recessive, Autosomal Recessive Juvenile Parkinson Disease, Recessive Parkinsonism, Autosomal, Mild Cognitive Impairments, Intellectual Development Disorder, Parkinsonian disease, Mild Cognitive, Cognitive Decline, MRXSH, Cognitive Impairment, Mental Deficiencies, Experimental Parkinson Diseases, Parkinson Disease 2, PRR, mouse, Impairments, Idiocy, with Diurnal Fluctuation, Autosomal Dominant Parkinsonism, Cistrons, Development Disorders, Psychosocial Mental, Juvenile, Psychosocial Mental Retardations, Experimental, Psychosocial Mental Retardation, Parkinsonian Syndromes, Mus, Cognitive Impairments, Mild Cognitive Impairment, XPDS, Diseases, MPTP Induced, Autosomal Recessive Parkinsonism, Genetic Materials, Progressive neurodegenerative disorder, Cognitive abnormality, Dysfunction, Parkinson Diseases, Genetic Material, Autosomal Dominant, ATP6IP2, Intellectual Development Disorders, XMRE, Mus musculus, Juvenile Parkinsonisms, Mental Deterioration, mice, Chromosome 6-Linked Autosomal Recessive Parkinsonism, Disability, Swiss Mouse, MPTP Induced Experimental Parkinsonism, House Mice, INSDC_feature:gene, Neurodegenerative disease, Cognitive, Intellectual Disability, domesticus, Laboratory Mice, Cognitive impairment, Early-Onset, Psychosocial, Experimental Parkinson Disease, Declines, Deficiency, Mental Deficiency, Parkinsonisms, Parkinsonian Syndrome, Juvenile Parkinsonism, Autosomal Recessive Juvenile Parkinsonism, Material, Experimental Parkinson, Psychosocial intellectual disability, Familial Juvenile, Autosomal Dominant Juvenile Parkinson Disease, Decline, Development Disorder, MSTP009, DEFIC MENTAL, Cistron, Mouse, Abnormality of cognition, Neuro-degenerative disease., Experimental Parkinsonisms, MPTP-Induced Experimental, MPTP-Induced Experimental Parkinsonism, Mental Retardations, Intellectual Development, Laboratory Mouse, Autosomal Dominant. Juvenile, Mental DeteriorationsMus musculus, Laboratory Mice., House, Mus, Laboratory, Swiss, Mus domesticus, mouse, Mus musculus domesticus, Swiss Mouse, mouse <Mus musculus>, Mouse, House Mice, Swiss Mice, house mouse, Mice, Laboratory Mouse, House Mouse, mice C57BL/6xCBA/CaJ hybrid, domesticus, Mus muscarisfalseMus musculusConditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration2025-09-242015-09-25PRJNA280215GSE675411009026376863