The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

被引：0
作者：
Erwan Lambert
Orthis Saha
Bruna Soares Landeira
Ana Raquel Melo de Farias
Xavier Hermant
Arnaud Carrier
Alexandre Pelletier
Johanna Gadaut
Lindsay Davoine
Cloé Dupont
Philippe Amouyel
Amélie Bonnefond
Frank Lafont
Farida Abdelfettah
Patrik Verstreken
Julien Chapuis
Nicolas Barois
Fabien Delahaye
Bart Dermaut
Jean-Charles Lambert
Marcos R. Costa
Pierre Dourlen
机构：
[1] Univ. Lille,Brain Institute
[2] Inserm,VIB Center for Brain and Disease Research
[3] CHU Lille,Department of Neurosciences, Leuven Brain Institute
[4] Institut Pasteur Lille,Department of Biomolecular Medicine, Faculty of Medicine and Health sciences
[5] U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement,Centre for Medical Genetics
[6] Federal University of Rio Grande do Norte,undefined
[7] Univ. Lille,undefined
[8] Inserm,undefined
[9] CNRS,undefined
[10] CHU Lille,undefined
[11] Institut Pasteur de Lille,undefined
[12] U1283-UMR 8199 EGID,undefined
[13] Univ. Lille,undefined
[14] CNRS,undefined
[15] Inserm,undefined
[16] CHU Lille,undefined
[17] Institut Pasteur de Lille,undefined
[18] U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille,undefined
[19] KU Leuven,undefined
[20] KU Leuven,undefined
[21] Univ. Lille,undefined
[22] CNRS,undefined
[23] Inserm,undefined
[24] CHU Lille,undefined
[25] Institut Pasteur de Lille,undefined
[26] US41-UMS2014-PLBS,undefined
[27] Ghent University,undefined
[28] Ghent University Hospital,undefined
来源：
Acta Neuropathologica Communications | / 10卷
关键词：
BIN1 isoforms; Neurodegeneration; Early endosome; Alzheimer’s disease; Drosophila; Human induced neurons;
D O I：
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学科分类号：
摘要：
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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