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

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 v...

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Published in:	Frontiers in cellular neuroscience Vol. 15; p. 803302
Main Authors:	Moreira, Danielle de Paula, Suzuki, Angela May, Silva, André Luiz Teles E, Varella-Branco, Elisa, Meneghetti, Maria Cecília Zorél, Kobayashi, Gerson Shigeru, Fogo, Mariana, Ferrari, Merari de Fátima Ramires, Cardoso, Rafaela Regina, Lourenço, Naila Cristina Vilaça, Griesi-Oliveira, Karina, Zachi, Elaine Cristina, Bertola, Débora Romeo, Weinmann, Karina de Souza, de Lima, Marcelo Andrade, Nader, Helena Bonciani, Sertié, Andrea Laurato, Passos-Bueno, Maria Rita
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Research Foundation 13-01-2022 Frontiers Media S.A
Subjects:	Amino acids Autism Autophagy Brain architecture Cell cycle Cell differentiation Cell migration clathrin early secretory pathway Encephalopathy Endoplasmic reticulum Epidermal growth factor Genetic counseling Genetic testing Genomes GM130 Golgi apparatus Intellectual disabilities Kinases Molecular modelling Neural stem cells Neurogenesis Neuroscience Phenotypes Plasmids Pluripotency Proteins STAM Stem cells TOR protein vesicle trafficking United States > US autophagy GM130 clathrin mTOR STAM early secretory pathway iPSC-neurodevelopmental disease modeling vesicle trafficking
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Annalisa Scimemi, University at Albany, United States This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience These authors have contributed equally to this work and share first authorship Reviewed by: Daisuke Mori, Nagoya University, Japan; Gaelle Boncompain, Institut Curie, France
ISSN:	1662-5102 1662-5102
DOI:	10.3389/fncel.2021.803302