論文

査読有り 国際誌
2019年4月15日

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

The Journal of clinical investigation
  • 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

129
5
開始ページ
2145
終了ページ
2162
記述言語
英語
掲載種別
研究論文(学術雑誌)
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.

リンク情報
DOI
https://doi.org/10.1172/JCI79990
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30985297
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486358
ID情報
  • DOI : 10.1172/JCI79990
  • PubMed ID : 30985297
  • PubMed Central 記事ID : PMC6486358

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