| Autor: |
Andrés Miguez, Cinta Gomis, Cristina Vila, Marta Monguió-Tortajada, Sara Fernández-García, Georgina Bombau, Mireia Galofré, María García-Bravo, Phil Sanders, Helena Fernández-Medina, Blanca Poquet, Cristina Salado-Manzano, Santiago Roura, Jordi Alberch, José Carlos Segovia, Nicholas D. Allen, Francesc E. Borràs, Josep M. Canals |
| Rok vydání: |
2022 |
| Popis: |
Huntington's disease (HD) is an incurable inherited brain disorder characterized by massive degeneration of striatal neurons, which correlates with abnormal accumulation of misfolded mutant huntingtin (mHTT) protein. Research on HD has been hampered by the inability to study early dysfunction and progressive degeneration of human striatal neurons in vivo. To investigate human pathogenesis in a physiologically relevant context, we transplanted human pluripotent stem cell-derived neural progenitor cells (hNPCs) from control and HD patients into the striatum of newborn mice. Chimeric mice were subjected to behavioral testing and implanted human cells were examined by immunohistochemistry and electron microscopy. Most hNPCs differentiated into striatal neurons that projected to their target areas and established synaptic connections within the host basal ganglia circuitry. Remarkably, HD human striatal neurons first developed mHTT oligomers, which primarily targeted endoplasmic reticulum, mitochondria and nuclear membrane to cause structural alterations. Furthermore, HD human cells secreted extracellular vesicles containing mHTT oligomers, which were internalized by non-mutated mouse striatal neurons triggering cell death. We conclude that interaction of mHTT oligomers with key cellular organelles initially drives disease progression in HD patients, and that mHTT oligomers within extracellular vesicles contribute to spread the disease in a non-cell autonomous manner. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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