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

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-LondonoMarion 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2145-2162
Number of pages18
JournalJournal of Clinical Investigation
Volume129
Issue number5
DOIs
Publication statusPublished - May 1 2019

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Proteolysis
Adenosine Triphosphatases
Brain
Neural Stem Cells
Carcinogenesis
Cell Death
Central Nervous System
Apoptosis
Neurons
Membranes
Proteins
In Vitro Techniques
Cell Self Renewal
lysosomal proteins

ASJC Scopus subject areas

  • Medicine(all)

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Hirose, T., Cabrera-Socorro, A., Chitayat, D., Lemonnier, T., Féraud, O., Cifuentes-Diaz, C., ... Groszer, M. (2019). ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration. Journal of Clinical Investigation, 129(5), 2145-2162. https://doi.org/10.1172/JCI79990

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration. / Hirose, Takuo; Cabrera-Socorro, Alfredo; Chitayat, David; Lemonnier, Thomas; Féraud, Olivier; Cifuentes-Diaz, Carmen; Gervasi, Nicolas; Mombereau, Cedric; Ghosh, Tanay; Stoica, Loredana; d’Arc Al Bacha, Jeanne; Yamada, Hiroshi; Lauterbach, Marcel A.; Guillon, Marc; Kaneko, Kiriko; Norris, Joy W.; Siriwardena, Komudi; Blasér, Susan; Teillon, Jérémie; Mendoza-Londono, Roberto; Russeau, Marion; Hadoux, Julien; Ito, Sadayoshi; Corvol, Pierre; Matheus, Maria G.; Holden, Kenton R.; Takei, Kohji; Emiliani, Valentina; Bennaceur-Griscelli, Annelise; Schwartz, Charles E.; Nguyen, Genevieve; Groszer, Matthias.

In: Journal of Clinical Investigation, Vol. 129, No. 5, 01.05.2019, p. 2145-2162.

Research output: Contribution to journalArticle

Hirose, T, Cabrera-Socorro, A, Chitayat, D, Lemonnier, T, Féraud, O, Cifuentes-Diaz, C, Gervasi, N, Mombereau, C, Ghosh, T, Stoica, L, d’Arc Al Bacha, J, Yamada, H, Lauterbach, MA, Guillon, M, Kaneko, K, Norris, JW, Siriwardena, K, Blasér, S, Teillon, J, Mendoza-Londono, R, Russeau, M, Hadoux, J, Ito, S, Corvol, P, Matheus, MG, Holden, KR, Takei, K, Emiliani, V, Bennaceur-Griscelli, A, Schwartz, CE, Nguyen, G & Groszer, M 2019, 'ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration', Journal of Clinical Investigation, vol. 129, no. 5, pp. 2145-2162. https://doi.org/10.1172/JCI79990
Hirose T, Cabrera-Socorro A, Chitayat D, Lemonnier T, Féraud O, Cifuentes-Diaz C et al. ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration. Journal of Clinical Investigation. 2019 May 1;129(5):2145-2162. https://doi.org/10.1172/JCI79990
Hirose, Takuo ; Cabrera-Socorro, Alfredo ; Chitayat, David ; Lemonnier, Thomas ; Féraud, Olivier ; Cifuentes-Diaz, Carmen ; Gervasi, Nicolas ; Mombereau, Cedric ; Ghosh, Tanay ; Stoica, Loredana ; d’Arc Al Bacha, Jeanne ; Yamada, Hiroshi ; Lauterbach, Marcel A. ; Guillon, Marc ; Kaneko, Kiriko ; Norris, Joy W. ; Siriwardena, Komudi ; Blasér, Susan ; Teillon, Jérémie ; Mendoza-Londono, Roberto ; Russeau, Marion ; Hadoux, Julien ; Ito, Sadayoshi ; Corvol, Pierre ; Matheus, Maria G. ; Holden, Kenton R. ; Takei, Kohji ; Emiliani, Valentina ; Bennaceur-Griscelli, Annelise ; Schwartz, Charles E. ; Nguyen, Genevieve ; Groszer, Matthias. / ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 5. pp. 2145-2162.
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T1 - ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration

AU - Hirose, Takuo

AU - Cabrera-Socorro, Alfredo

AU - Chitayat, David

AU - Lemonnier, Thomas

AU - Féraud, Olivier

AU - Cifuentes-Diaz, Carmen

AU - Gervasi, Nicolas

AU - Mombereau, Cedric

AU - Ghosh, Tanay

AU - Stoica, Loredana

AU - d’Arc Al Bacha, Jeanne

AU - Yamada, Hiroshi

AU - Lauterbach, Marcel A.

AU - Guillon, Marc

AU - Kaneko, Kiriko

AU - Norris, Joy W.

AU - Siriwardena, Komudi

AU - Blasér, Susan

AU - Teillon, Jérémie

AU - Mendoza-Londono, Roberto

AU - Russeau, Marion

AU - Hadoux, Julien

AU - Ito, Sadayoshi

AU - Corvol, Pierre

AU - Matheus, Maria G.

AU - Holden, Kenton R.

AU - Takei, Kohji

AU - Emiliani, Valentina

AU - Bennaceur-Griscelli, Annelise

AU - Schwartz, Charles E.

AU - Nguyen, Genevieve

AU - Groszer, Matthias

PY - 2019/5/1

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N2 - 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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