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.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alternative Splicing
  • Animals
  • Apoptosis
  • Brain / diagnostic imaging
  • Cell Death
  • Cell Differentiation
  • Cell Survival
  • Central Nervous System / physiopathology*
  • Child, Preschool
  • Gene Deletion
  • Genetic Variation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / metabolism
  • Neurodegenerative Diseases / diagnostic imaging*
  • Neurodegenerative Diseases / genetics*
  • Neurons / metabolism
  • Pluripotent Stem Cells / metabolism*
  • Proton-Translocating ATPases / genetics
  • Proton-Translocating ATPases / physiology
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / physiology
  • Vacuolar Proton-Translocating ATPases / genetics*
  • Vacuolar Proton-Translocating ATPases / physiology


  • ATP6AP2 protein, human
  • ATP6AP2 protein, mouse
  • Receptors, Cell Surface
  • Vacuolar Proton-Translocating ATPases
  • Proton-Translocating ATPases