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

J Clin Invest. 2019 Apr 15;129(5):2145-2162. doi: 10.1172/JCI79990.

Takuo Hirose ¹, Alfredo Cabrera-Socorro ² ³ ⁴, David Chitayat ⁵ ⁶ ⁷, Thomas Lemonnier ² ³ ⁴, Olivier Féraud ⁸ ⁹, Carmen Cifuentes-Diaz ² ³ ⁴, Nicolas Gervasi ² ³ ⁴, Cedric Mombereau ² ³ ⁴, Tanay Ghosh ² ³ ⁴, Loredana Stoica ² ³ ⁴, Jeanne d'Arc Al Bacha ¹ ³ ⁴ ¹⁰ ¹¹, Hiroshi Yamada ¹², Marcel A Lauterbach ¹³, Marc Guillon ¹³, Kiriko Kaneko ¹⁴, Joy W Norris ¹⁵, Komudi Siriwardena ⁶, Susan Blasér ⁶, Jérémie Teillon ¹ ¹⁶ ¹⁷, Roberto Mendoza-Londono ⁶, Marion Russeau ² ³ ⁴, Julien Hadoux ⁸ ⁹, Sadayoshi Ito ¹⁸, Pierre Corvol ¹ ¹⁶ ¹⁷, Maria G Matheus ¹⁹, Kenton R Holden ²⁰, Kohji Takei ¹², Valentina Emiliani ¹³, Annelise Bennaceur-Griscelli ⁸ ⁹ ²¹ ²², Charles E Schwartz ¹⁵, Genevieve Nguyen ¹ ¹⁶ ¹⁷, Matthias Groszer ² ³ ⁴

Affiliations

1 Collège de France, Center for Interdisciplinary Research in Biology, Paris, France.
2 INSERM, UMR-S 1270, Paris, France.
3 Sorbonne Université, Paris, France.
4 Institut du Fer à Moulin, Paris, France.
5 Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
6 Division of Clinical and Metabolic Genetics and.
7 Department of Diagnostic Imaging, Division of Pediatric Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
8 INSERM, UMR 935, ESTeam Paris Sud, SFR André Lwoff, Université Paris Sud, Villejuif, France.
9 Infrastructure Nationale INGESTEM, Université Paris Sud, INSERM, Paris, France.
10 Laboratory of Applied Biotechnology, Azm Center for the Research in Biotechnology and Its Applications, Doctoral School for Sciences and Technology, Lebanese University, Tripoli, Lebanon.
11 Reviva Regenerative Medicine Center, Human Genetic Center, Middle East Institute of Health Hospital, Bsalim, Lebanon.
12 Department of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
13 Wavefront-Engineering Microscopy Group, Neurophotonics Laboratory, CNRS, UMR 8250, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
14 Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
15 Greenwood Genetic Center, Greenwood, South Carolina, USA.
16 INSERM, U1050, Paris, France.
17 CNRS, UMR 7241, Paris, France.
18 Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
19 Department of Neurosciences (Neurology) and.
20 Department of Radiology, Medical University of South Carolina, Charleston, South Carolina, USA.
21 Faculté de Médecine, Kremlin-Bicêtre, Université Paris Sud, Paris Saclay, France.
22 AP-HP, Service d'Hématologie, Hôpitaux Universitaires Paris Sud, Hôpital Paul Brousse, Villejuif, France.

PMID: 30985297 DOI: 10.1172/JCI79990

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.

Keywords

Genetic diseases; Genetics; Neurodegeneration; Neurodevelopment; Neuroscience.

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