Atp6v1a-flox Mouse

Atp6v1a, the ATPase, H+ transporting, lysosomal V1 subunit A, is a component of the cytosolic V1 domain of the proton pump vacuolar ATPase (V-ATPase). V-ATPase is a multimeric complex present in various cellular membranes, acting as an ATP-dependent proton pump crucial for pH homeostasis and intracellular signalling pathways [2].

In murine hippocampal neurons, depletion of Atp6v1a affects neurite elongation, stabilization, and the function of excitatory synapses, and prevents synaptic rearrangement upon induction of plasticity. This is due to decreased expression of V1 subunits, impairment of lysosomal pH-regulation, and autophagy progression, with accumulation of aberrant lysosomes and enlarged vacuoles [1].

In humans, pathogenic de novo missense ATP6V1A variants are associated with a range of phenotypes. These include early lethal encephalopathies with brain atrophy, severe developmental epileptic encephalopathies, and static intellectual disability with epilepsy. Fibroblasts from patients show lysosomal impairment and abnormal organelle pH, and electron microscopy reveals abnormal inclusions [2]. Additionally, in childhood epilepsy, ATP6V1A variants can be associated with different phenotypes, with monoallelic missense variants linked to epilepsy of variable severity, and biallelic variants resulting in multisystem developmental abnormalities [3].

In conclusion, Atp6v1a is essential for maintaining lysosomal function, synaptic integrity, and plasticity. Studies using mouse models and human patient samples have revealed its crucial role in neurodevelopment and the pathophysiology of neurodevelopmental and neurodegenerative diseases. Understanding the function of Atp6v1a through these models provides insights into the underlying mechanisms of related disorders, which may potentially guide the development of new therapeutic strategies.