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

Frontiers in Cellular Neuroscience

Maria Rita Passos-Bueno¹  Karina de Souza Weinmann¹  Naila Cristina Vilaça Lourenço¹  Elisa Varella-Branco¹  Gerson Shigeru Kobayashi¹  Elaine Cristina Zachi¹  Danielle de Paula Moreira¹  Angela May Suzuki¹  Maria Cecília Zorél Meneghetti²  Marcelo Andrade de Lima²  Helena Bonciani Nader²  Rafaela Regina Cardoso³  Merari de Fátima Ramires Ferrari³  Débora Romeo Bertola⁴  Karina Griesi-Oliveira⁵  Mariana Fogo⁵  André Luiz Teles e Silva⁵  Andrea Laurato Sertié⁵ 

[1] Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil;Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil;Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil;Instituto da Criança do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil;Instituto de Ensino e Pesquisa Albert Einstein, Albert Einstein Hospital, São Paulo, Brazil;

关键词: STAM;    early secretory pathway;    vesicle trafficking;    autophagy;    GM130;    clathrin;   

DOI  :  10.3389/fncel.2021.803302

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown