Frontiers in Cellular Neuroscience (Jan 2022)

Neuroprogenitor Cells From Patients With TBCK Encephalopathy Suggest Deregulation of Early Secretory Vesicle Transport

  • Danielle de Paula Moreira,
  • Angela May Suzuki,
  • André Luiz Teles e Silva,
  • Elisa Varella-Branco,
  • Maria Cecília Zorél Meneghetti,
  • Gerson Shigeru Kobayashi,
  • Mariana Fogo,
  • Mariana Fogo,
  • Merari de Fátima Ramires Ferrari,
  • Rafaela Regina Cardoso,
  • Naila Cristina Vilaça Lourenço,
  • Karina Griesi-Oliveira,
  • Karina Griesi-Oliveira,
  • Elaine Cristina Zachi,
  • Débora Romeo Bertola,
  • Débora Romeo Bertola,
  • Karina de Souza Weinmann,
  • Marcelo Andrade de Lima,
  • Helena Bonciani Nader,
  • Andrea Laurato Sertié,
  • Maria Rita Passos-Bueno

DOI
https://doi.org/10.3389/fncel.2021.803302
Journal volume & issue
Vol. 15

Abstract

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Biallelic pathogenic variants in TBCK cause encephaloneuropathy, infantile hypotonia with psychomotor retardation, and characteristic facies 3 (IHPRF3). The molecular mechanisms underlying its neuronal phenotype are largely unexplored. In this study, we reported two sisters, who harbored biallelic variants in TBCK and met diagnostic criteria for IHPRF3. We provided evidence that TBCK may play an important role in the early secretory pathway in neuroprogenitor cells (iNPC) differentiated from induced pluripotent stem cells (iPSC). Lack of functional TBCK protein in iNPC is associated with impaired endoplasmic reticulum-to-Golgi vesicle transport and autophagosome biogenesis, as well as altered cell cycle progression and severe impairment in the capacity of migration. Alteration in these processes, which are crucial for neurogenesis, neuronal migration, and cytoarchitecture organization, may represent an important causative mechanism of both neurodevelopmental and neurodegenerative phenotypes observed in IHPRF3. Whether reduced mechanistic target of rapamycin (mTOR) signaling is secondary to impaired TBCK function over other secretory transport regulators still needs further investigation.

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