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ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration
Takuo Hirose, … , Genevieve Nguyen, Matthias Groszer
Takuo Hirose, … , Genevieve Nguyen, Matthias Groszer
Published April 15, 2019
Citation Information: J Clin Invest. 2019;129(5):2145-2162. https://doi.org/10.1172/JCI79990.
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Research Article Genetics Neuroscience

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration

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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.

Authors

Takuo Hirose, Alfredo Cabrera-Socorro, David Chitayat, Thomas Lemonnier, Olivier Féraud, Carmen Cifuentes-Diaz, Nicolas Gervasi, Cedric Mombereau, Tanay Ghosh, Loredana Stoica, Jeanne d’Arc Al Bacha, Hiroshi Yamada, Marcel A. Lauterbach, Marc Guillon, Kiriko Kaneko, Joy W. Norris, Komudi Siriwardena, Susan Blasér, Jérémie Teillon, Roberto Mendoza-Londono, Marion Russeau, Julien Hadoux, Sadayoshi Ito, Pierre Corvol, Maria G. Matheus, Kenton R. Holden, Kohji Takei, Valentina Emiliani, Annelise Bennaceur-Griscelli, Charles E. Schwartz, Genevieve Nguyen, Matthias Groszer

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Figure 6

Abnormal “in vitro corticogenesis” of patient iPSC-derived neurons.

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Abnormal “in vitro corticogenesis” of patient iPSC-derived neurons.
(A) ...
(A) Left: Laminar organization of proliferative and differentiation compartments of “cortical” rosettes derived from control and patient iPSCs after 20 days in vitro (DIV). Normal expression pattern of apical marker PAR3 and adherens junctions markers CDH2 and CTNNB1. AP, apical pole; L, lumen. Scale bars: 10 μm. Right: Phospho–histone 3 (pH3) immunostaining did not reveal differences in progenitor proliferation between control and patient. Data show individual values and mean ± SEM; n = 12 per group. P = 0.341 (ns), Student’s t test (unpaired, 2-tailed). (B) Immunostaining with PAX6 and TUJ1 shows interspersed neurons in the progenitor zone of patient-derived rosettes. This phenotype is rescued by re-expression of fl-ATP6AP2. Lines: luminal surface. Scale bars: 25 μm. (C) Significantly increased median pH in patient cells in early differentiating neurons. Data show individual values and median; n = 463–550 measurements from 5 independent experiments. ***P < 0.001, Kruskal-Wallis test (χ2 = 245.97, df = 4, P < 0.001) followed by Dunn’s multiple-comparisons test.
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