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

Moreira, DDP; Suzuki, AM; Silva, ALTE; Varella-Branco, E; Meneghetti, MCZ; Kobayashi, GS; Fogo, M; Ferrari, MDFR; Cardoso, RR; Lourenço, NCV; Griesi-Oliveira, K; Zachi, EC; Bertola, DR; Weinmann, KDS; Andrade De Lima, Marcelo; Nader, HB; Sertié, AL; Passos-Bueno, MR

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


Authors

DDP Moreira

AM Suzuki

ALTE Silva

E Varella-Branco

MCZ Meneghetti

GS Kobayashi

M Fogo

MDFR Ferrari

RR Cardoso

NCV Lourenço

K Griesi-Oliveira

EC Zachi

DR Bertola

KDS Weinmann

HB Nader

AL Sertié

MR Passos-Bueno



Abstract

<jats:p>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.</jats:p>

Journal Article Type Article
Acceptance Date Dec 15, 2021
Online Publication Date Jan 13, 2022
Publication Date 2022-02
Publicly Available Date Mar 28, 2024
Journal Frontiers in Cellular Neuroscience
Electronic ISSN 1662-5102
Publisher Frontiers Media
Volume 15
DOI https://doi.org/10.3389/fncel.2021.803302
Publisher URL https://www.frontiersin.org/articles/10.3389/fncel.2021.803302/full

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