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

Abstract

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.

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration

“…The failure to detect a broad range of apical proteins in Atp6ap2 cKOs suggested severe deficits in fundamental cellular processes such as protein trafficking, recycling, or degradation interfering with multiple signaling pathways. This is supported by studies in mice with conditional Atp6ap2 deletion in postnatal neurons (19), cardiomyocytes (9), or podocytes (10,25) showing impaired autophagy and increased cell death.…”

“…However, the blood pressure in XLID patients carrying ATP6AP2 (c.321C>T, p.D107D) was normal (18). Another study in mice carrying a conditional postnatal Atp6ap2 deletion in postmitotic neurons has identified autophagy deficits associated with impairments of synaptic plasticity, myelination, and memory functions (19).…”

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

“…Similar effects of v-ATPase impairment follow the conditional deletion of the ATP6AP2 gene (which encodes for a critical v-ATPase-regulating protein). Loss of ATP6AP2 , which reduces v-ATPase activity (Korvatska et al, 2013), led to neurodegeneration and cognitive impairment in both fly and mouse models, along with the appearance of autophagic vacuoles, suggesting a failure of lysosomal proteolysis (Dubos et al, 2015). These animal models highlight the importance of the v-ATPase and lysosomal acidification in the aging brain, as v-ATPase defects are sufficient to induce neuropathological phenotypes similar to those observed in AD and PD.…”

“…Mutations in exon 4 of the ATP6AP2 gene (c.321C>T), leading to altered ATP6AP2 splicing, are also linked to another neurological condition, X-linked Mental Retardation Hedera type (MRXSH) (Hedera et al, 2002; Ramser et al, 2005), a congenital form of mental retardation with epilepsy and sometimes ataxia (Hedera et al, 2002). Recently, conditional CNS-specific knockdown of ATP6AP2 was shown to cause cognitive impairment, neurodegeneration, and autophagy failure in both mouse and fly models (Dubos et al, 2015). …”

Genetic strategies to tackle neurological diseases in fruit flies

“…Recent examples include models of Parkinson’s disease (PD) [18], amyotropic lateral sclerosis (ALS) [19], Coffin-Lowry syndrome [20], and lysosomal storage diseases (LSDs) [21]. Similarly, RNAi mediated knockdown has been successfully utilized to assess the in vivo function of disease-associated genes including parkin [22] , valosin containing protein (VCP) [23] , amyloid precursor protein (APP) [24], and others [25,26]. …”