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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 May 1, 2019; First published April 15, 2019
Citation Information: J Clin Invest. 2019;129(5):2145-2162. https://doi.org/10.1172/JCI79990.
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Categories: 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 1

Fulminant neurodegeneration in patient carrying ATP6AP2 (c.301-11_301-10delTT) variant.

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Fulminant neurodegeneration in patient carrying ATP6AP2 (c.301-11_301-10...
(A) Sequential brain MRI of patient 1 carrying the ATP6AP2 (c.301-11_301-10delTT) variant at 5 weeks, 9 months, and 28 months of age. Sagittal (left) and axial (right) T1-weighted MR images at 5 weeks showed a thin, poorly developing corpus callosum (arrow) and diffuse volume loss of the brain parenchyma, enlarged ventricles, and prominent sulci. At 9 months the MRI revealed delayed myelination, a persistently thin hypoplastic corpus callosum (arrow), and parenchymal volume loss. At 28 months the MRI showed a markedly thin corpus callosum (arrow), minimal myelination throughout the brain, and significant parenchymal gray and white matter volume losses. (B) ATP6AP2 genomic organization and position of c.301-11_301-10delTT variant. Red arrows: primers used for RT-PCR. (C) Chromatogram of genomic DNA sequencing shows TT deletion in ATP6AP2 in the affected individual. (D) Chromatogram of cDNA sequencing shows exon 4 deletion. (E) RT-PCR analysis of patient fibroblast with fl-ATP6AP2 and a shorter product representing approximately 80% of ATP6AP2 transcripts. Lane 1, patient; lane 2, control; lane 3, H2O.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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