期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 10, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s40478-021-01285-5
关键词
BIN1 isoforms; Neurodegeneration; Early endosome; Alzheimer's disease; Drosophila; Human induced neurons
资金
- NIH [2P40OD010949, P40OD018537]
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- France Alzheimer [1999 BIN1DROSO]
- Fondation Vaincre Alzheimer (LECMA Grant) [ALZ201912009628, ALZ201906008477]
- European Union under the European Regional Development Fund (ERDF)
- Hauts de France Regional Council [18006176]
- MEL [contract_2016_ESR_05]
- French State [2018-3-CTRL_IPL_Phase2]
- Lille Metropole Communaute Urbaine
- French government's LABEX DISTALZ program
- ANR Equipex 2010 session [ANR-10-LABX-46, ANR-10-EQPX-07-01]
- FEDER
- Region Nord-Pas-de-Calais-Picardie
This study reveals that the isoform BIN1iso1 of the Alzheimer's disease susceptibility gene BIN1 plays a role in the deregulation of early endosome size, contributing to the early pathophysiological hallmark of AD.
The 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 human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (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.
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