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

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Moreira, Danielle de Paula ; Suzuki, Angela May ; Teles e Silva, Andre Luiz ; Varella-Branco, Elisa ; Zorel Meneghetti, Maria Cecilia ; Kobayashi, Gerson Shigeru ; Fogo, Mariana ; Ramires Ferrari, Merari de Fatima ; Cardoso, Rafaela Regina ; Vilaca Lourenco, Naila Cristina ; Griesi-Oliveira, Karina ; Zachi, Elaine Cristina ; Bertola, Debora Romeo ; Weinmann, Karina de Souza ; de Lima, Marcelo Andrade ; Nader, Helena Bonciani ; Sertie, Andrea Laurato ; Passos-Bueno, Maria Rita

• Document type: Journal article
• Source: FRONTIERS IN CELLULAR NEUROSCIENCE; v. 15, p. 15-pg., 2022-01-13.

Abstract

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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC