| Autor: |
Erwan Lambert, Bart Dermaut, Nicolas Barois, Julien Chapuis, Farida Adelfettah, Pierre Dourlen, Fabien Delahaye, Patrik Verstreken, Philippe Amouyel, Amélie Bonnefond, Xavier Hermant, Arnaud Carrier, Marcos Romualdo Costa, Cloé Dupont, Alexandre Pelletier, Orthis Saha, Lindsay Davoine, Jean-Charles Lambert, Ana Raquel Melo de Farias, Bruna Soares Landeira, Frank Lafont |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
SUMMARYThe Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to BIN1iso8 and BIN1iso9, induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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