ArticleThe Journal of clinical investigation2019
ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 56 citations in OpenAlex.
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- Cross-species analysis of adult hippocampal neurogenesis reveals human-specific gene expression but convergent biological processes.Nature neuroscience · 2025Article
- V-ATPase and Lysosomal Energy Sensing in Periodontitis and Medicine-Related Osteonecrosis of the Jaw.Biomolecules · 2025Review
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- Biomarker discovery in progressive supranuclear palsy from human cerebrospinal fluid.Clinical proteomics · 2024Article
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- Advances in Drug Discovery Targeting Lysosomal Membrane Proteins.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Effects of a monoclonal antibody against (pro)renin receptor on gliomagenesis.Scientific reports · 2023Article
- Synonymous variants in theFrontiers in neurology · 2023Article
- Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.Physiological reviews · 2023Review
- Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.Frontiers in molecular neuroscience · 2023Review
- Endothelial cell polarity and extracellular matrix composition require functional ATP6AP2 during developmental and pathological angiogenesis.JCI insight · 2022Article
- Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis.Brain : a journal of neurology · 2022Article
- Review
- Reduced gene dosage is a common mechanism of neuropathologies caused by ATP6AP2 splicing mutations.Parkinsonism & related disorders · 2022Article
- ATP6AP2 knockdown in cardiomyocyte deteriorates heart function via compromising autophagic flux and NLRP3 inflammasome activation.Cell death discovery · 2022Article
Corrections and comments
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Authors and funding
32 authors at 12 institutions in 5 countries.
Funding
Abstract
Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.
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Registered trials
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