ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration
| Autor: | Alfredo Cabrera-Socorro, Julien Hadoux, Carmen Cifuentes-Diaz, Marcel A. Lauterbach, Tanay Ghosh, Jérémie Teillon, Jeanne d’Arc Al Bacha, Nicolas Gervasi, Thomas Lemonnier, Pierre Corvol, David Chitayat, Susan Blaser, Kiriko Kaneko, Kohji Takei, Annelise Bennaceur-Griscelli, Marion Russeau, Komudi Siriwardena, Maria Matheus, Marc Guillon, Matthias Groszer, Valentina Emiliani, Loredana Stoica, Hiroshi Yamada, Olivier Feraud, Charles E. Schwartz, Joy Norris, Cedric Mombereau, Geneviève Nguyen, Kenton R. Holden, Sadayoshi Ito, Roberto Mendoza-Londono, Takuo Hirose |
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| Rok vydání: | 2019 |
| Předmět: |
Central Nervous System
Male Pluripotent Stem Cells 0301 basic medicine Vacuolar Proton-Translocating ATPases Programmed cell death Adolescent Cell Survival Central nervous system Apoptosis Receptors Cell Surface Protein degradation Biology Mice 03 medical and health sciences 0302 clinical medicine Neural Stem Cells medicine Animals Humans Induced pluripotent stem cell Neurons ATP6AP2 Cell Death Neurodegeneration Brain Genetic Variation Cell Differentiation Neurodegenerative Diseases General Medicine medicine.disease Neural stem cell Cell biology Mice Inbred C57BL Alternative Splicing Proton-Translocating ATPases HEK293 Cells 030104 developmental biology Proteostasis medicine.anatomical_structure Child Preschool 030220 oncology & carcinogenesis Lysosomes Gene Deletion HeLa Cells Research Article |
| Zdroj: | Journal of Clinical Investigation. 129:2145-2162 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci79990 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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