The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects
Year: 2021
Type: preprint
Abstract: SUMMARY 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 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.
Authors: Erwan Lambert, Orthis Saha, Bruna Soares Landeira, Ana Raquel Melo de Farias, Xavier Hermant, Arnaud Carrier, Alexandre Pelletier, Lindsay Davoine, Cloé Dupont, Philippe Amouyel, Amélie Bonnefond, Frank Lafont, Farida Adelfettah, Patrik Verstreken, Julien Chapuis, Nicolas Barois, Fabien Delahaye, Bart Dermaut, Jean-Charles Lambert, Marcos R. Costa, Pierre Dourlen
Institutions: Inserm, Université de Lille, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Approches épidémiologiques et moléculaires intégratives visant à améliorer la compréhension des maladies chroniques liées au vieillissement, Universidade Federal do Rio Grande do Norte, Centre National de la Recherche Scientifique, European Genomic Institute for Diabetes, Center for Infection and Immunity of Lille, VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, Ghent University Hospital
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Johns Hopkins University, Fondation Vaincre Alzheimer, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, Equipex, European Genomic Institute for Diabetes, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Bordeaux, National Institutes of Health, European Regional Development Fund, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
OpenAlex ID: W3148901355