| Autor: |
Alejandra Suárez-Carrillo, Mónica Álvarez-Córdoba, Ana Romero-González, Marta Talaverón-Rey, Suleva Povea-Cabello, Paula Cilleros-Holgado, Rocío Piñero-Pérez, Diana Reche-López, David Gómez-Fernández, José M. Romero-Domínguez, Manuel Munuera-Cabeza, Antonio Díaz, Susana Gonzalez-Granero, José M. García-Verdugo, And José A. Sánchez-Alcázar |
| Rok vydání: |
2023 |
| Popis: |
Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic dis-orders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β -propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate autophagic defects and secondary pathological con-sequences in cellular models derived from two patient harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibro-blasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. Transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron ac-cumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochon-drial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the ex-pression levels of WDR45 neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidant partially improved cell physiopathology, however autophagy and cell bioenergetics remained affected. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
