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

• Published in: Acta neuropathologica communications Vol. 10; no. 1; p. 4
• Main Authors: Lambert, Erwan, Saha, Orthis, Soares Landeira, Bruna, Melo de Farias, Ana Raquel, Hermant, Xavier, Carrier, Arnaud, Pelletier, Alexandre, Gadaut, Johanna, Davoine, Lindsay, Dupont, Cloé, Amouyel, Philippe, Bonnefond, Amélie, Lafont, Frank, Abdelfettah, Farida, Verstreken, Patrik, Chapuis, Julien, Barois, Nicolas, Delahaye, Fabien, Dermaut, Bart, Lambert, Jean-Charles, Costa, Marcos R, Dourlen, Pierre
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08.01.2022; BioMed Central; BioMed Central part of Springer Science; BMC
• Subjects: Advertising executives; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Animals, Genetically Modified; Antibodies; BIN1 isoforms; Binding sites; Brain - metabolism; Brain - pathology; Disease susceptibility; Drosophila; Drosophila melanogaster; Drosophila Proteins - genetics; Early endosome; Endosomes - genetics; Endosomes - metabolism; Endosomes - pathology; Genetic aspects; Human induced neurons; Humans; Induced Pluripotent Stem Cells - metabolism; Insects; Life Sciences; Membranes; Molecular weight; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Neurodegeneration; Neurons - metabolism; Neurons - pathology; Neurotoxicity; Proteins; Software; Transcription Factors - genetics; France; United States > US; Germany; Human induced neurons; Alzheimer’s disease; Neurodegeneration; Drosophila; Early endosome; BIN1 isoforms
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-021-01285-5

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.