ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration
Open accessAbstract
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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ATP6AP2 encodes a protein essential for lysosomal degradative functions.
“ATP6AP2, one of the most downregulated genes in risk-allele iMGs (Fig. 4b and Supplementary Table 13), encodes a protein that is essential for lysosomal degradative functions; Atp6ap2-mutant mice show increased triglycerides and LD in fat body cells48.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [48]
Atp6ap2-mutant mice show increased triglycerides and LD in fat body cells.
“Atp6ap2-mutant mice show increased triglycerides and LD in fat body cells48.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [48]
The Results (pp. 5–7) describe Atp6ap2-mutant mice with enlarged lysosomes and accumulated autophagy-related structures in cortical and hippocampal cells. Searches for triglycerides, lipid droplets, and fat body cells found no passage addressing the claimed increases. (LLM, conf=0.75)
Experimental — accuracy not yet measuredGaucher Disease is the most common LSD.
“Gaucher Disease (GD), the most common LSD, exemplifies the complexity of this group’s presentations, ranging from perinatal lethality to mildly symptomatic.70”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [70]
The Discussion (pp. 11–12) addresses ATP6AP2-related neurodegeneration and lysosomal dysfunction, not Gaucher disease. Searches for “Gaucher” and “most common lysosomal storage disorder” found no passage in our copy supporting the claim or the cited sentence’s description of Gaucher disease’s presentations. (LLM, conf=0.75)
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References 80 · Cited by 55
Research works printed but not linked: 3
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- Authors
- Hirose, T., Cabrera-Socorro, A., Chitayat, D., Lemonnier, T., Féraud, O., Cifuentes-Diaz, C., Gervasi, N., Mombereau, C., Ghosh, T., Stoica, L., Bacha, J. D. A., Yamada, H., Lauterbach, M. A., Guillon, M., Kaneko, K., Norris, J. W., Siriwardena, K., Blasér, S., Teillon, J., Mendoza-Londono, R., Russeau, M., Hadoux, J., Ito, S., Corvol, P., Matheus, M. G., Holden, K. R., Takei, K., Emiliani, V., Bennaceur-Griscelli, A., Schwartz, C. E., Nguyen, G., & Groszer, M.
- Affiliations
- Collège de France (FR)
- Mount Sinai Hospital (CA)
- Inserm (FR)
- Université Paris-Sud (FR)
- Lebanese University (LB)
- Okayama University (JP)
- Centre National de la Recherche Scientifique (FR)
- Tohoku University (JP)
- Greenwood Genetic Center (US)
- Medical University of South Carolina (US)
- Corresponding author
- Groszer, Matthias
- ORCID
- Hirose, Takuo
- Chitayat, David
- Lemonnier, Thomas
- Cifuentes-Diaz, Carmen
- Gervasi, Nicolas
- Ghosh, Tanay
- Yamada, Hiroshi
- Lauterbach, Marcel A.
- Guillon, Marc
- Norris, Joy W.
- Blasér, Susan
- Teillon, Jérémie
- Mendoza-Londono, Roberto
- Russeau, Marion
- Hadoux, Julien
- Ito, Sadayoshi
- Matheus, Maria G.
- Takei, Kohji
- Emiliani, Valentina
- Schwartz, Charles E.
- Groszer, Matthias
- Venue
- Journal of Clinical Investigation
- Published
- 2019-04-15
- Volume
- 129
- Issue
- 5
- Pages
- 2145-2162
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6486358
- OpenAlex
- W2936477178
- Cited by
- 55
- References
- 80
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 10 · 2021: 7 · 2020: 11 · 2019: 2
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Investissements d’Avenir/ program (11-IDEX-0004-02)
- Association ‘Vaincre les Maladies Lysosomales-VML (VML 2016-1004)
- Fondation pour la Recherche Médicale ‘Schizo Oui’ (R12062DD)
- DIM Biothérapies-Stem-Pôle (DIM2011)
- Fondation Lejeune (#1389)
- European Union’s Seventh Framework Programme (PIEF-GA-2011-297917)
- Japan Science and Technology Agency (CREST program)
- NIH Clinical Center (R01NS073854)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- ATP6AP2, V-ATPase, vacuolar H+-ATPase, neurodegeneration, lysosomal acidification, protein degradation, neuronal survival, neural stem cell self-renewal, iPSC-derived neurons, central nervous system development, cortical degeneration
- MeSH terms
- Prorenin Receptor, Adolescent, Animals, Brain, Cell Differentiation, Cell Survival, Central Nervous System, Child, Preschool, Proton-Translocating ATPases, HeLa Cells, Humans, Lysosomes, Male, Mice, Inbred C57BL, Neurons, Receptors, Cell Surface, Genetic Variation, Cell Death, Apoptosis, Gene Deletion, Alternative Splicing, Neurodegenerative Diseases, Vacuolar Proton-Translocating ATPases, Pluripotent Stem Cells, Mice, HEK293 Cells, Neural Stem Cells
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