ATP6V1A, also known as ATPase, H+ transporting, lysosomal V1 subunit A, is a component of the cytosolic V1 domain of the vacuolar ATPase proton pump. This pump is crucial for pH homeostasis and intracellular signaling pathways, playing a vital role in various cellular functions [3].

In murine hippocampal neurons, depletion of Atp6v1a affects neurite elongation, stabilization, and excitatory synapse function, preventing synaptic rearrangement during plasticity induction. This is due to decreased V1 subunit expression, impairing lysosomal pH-regulation and autophagy progression, with aberrant lysosome and enlarged vacuole accumulation [1]. In humans, ATP6V1A variants are associated with a range of phenotypes. Monoallelic missense variants can lead to epilepsy with variable severity, while biallelic variants may result in multisystem developmental abnormalities and early lethality. Some patients with childhood focal epilepsy have shown good responses to anti-seizure medication [2]. Patients with ATP6V1A-related encephalopathy present with a spectrum of clinical pictures from early-lethal encephalopathies to static intellectual disability with epilepsy, along with features like microcephaly and amelogenesis imperfecta. Fibroblasts from affected patients show lysosomal impairment [3].

In conclusion, Atp6v1a is essential for maintaining synaptic integrity and plasticity, and its dysfunction is associated with neurodevelopmental and neurodegenerative diseases. Mouse models, especially those with Atp6v1a depletion, have been instrumental in understanding its role in neuronal development and function, while human genetic studies have revealed the genotype-phenotype correlations in diseases related to ATP6V1A variants.

References:

1. Esposito, Alessandro, Pepe, Sara, Cerullo, Maria Sabina, Falace, Antonio, Fassio, Anna. 2024. ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons. In Acta physiologica (Oxford, England), 240, e14186. doi:10.1111/apha.14186. https://pubmed.ncbi.nlm.nih.gov/38837572/

2. Li, Bin, Lan, Song, Liu, Xiao-Rong, Wang, Jie, Tian, Yang. 2023. ATP6V1A variants are associated with childhood epilepsy with favorable outcome. In Seizure, 116, 81-86. doi:10.1016/j.seizure.2023.08.004. https://pubmed.ncbi.nlm.nih.gov/37574426/

3. Guerrini, Renzo, Mei, Davide, Kerti-Szigeti, Katalin, Novarino, Gaia, Fassio, Anna. . Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis. In Brain : a journal of neurology, 145, 2687-2703. doi:10.1093/brain/awac145. https://pubmed.ncbi.nlm.nih.gov/35675510/