Autophagy and ER-stress in BPAN: insights from the Dictyostelium model
| Autor: | Escalante, Ricardo, Tornero-Écija, Alba, Tábara, Luis-Carlos, Bueno Arribas, M., Antón-Esteban, Laura, Navarro-Gómez, Cristina, Sánchez, Irene, Blanca, Irene, Cruz-Cuevas, Celia, Navas, María-Angeles, Vincent, Olivier |
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| Rok vydání: | 2022 |
| Popis: | Trabajo presentado en First BPAN disease symposium in France, celebrado en Lyon (Francia) del 13 al 14 de mayo de 2022. WIPIs are a conserved family of proteins with a characteristic 7-bladed b-helix structure. Mutations in human WIPI4 cause BPAN, a rare disease characterized by developmental delay, motor disorders and seizures. The pathological mechanisms leading to BPAN are still unclear and it has been proposed that autophagy, mitochondria homeostasis and endoplasmic reticulum (ER) stress are involved. We have generated a KO mutant in the WIPI4 homologue of Dictyostelium, Wdr45l. This mutant exhibits a complete block in autophagy that is associated with additional phenotypes: increased PI3P, growth arrest, and chronic activation of ER stress. PI3P accumulation is responsible for the growth arrest and chronic ER stress response and can therefore be considered as a potential therapeutic target. We have also analyzed the functionality of a number of pathological variants of WIPI4 with nonsense. Our results show that some of these mutations affect the subcellular localization of the protein, while others impair ATG2 binding. |
| Databáze: | OpenAIRE |
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