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

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dc.contributor.authorLambert, Erwan
dc.contributor.authorSaha, Orthis
dc.contributor.authorLandeira, Bruna Soares
dc.contributor.authorFarias, Ana Raquel Melo de
dc.contributor.authorHermant, Xavier
dc.contributor.authorCarrier, Arnaud
dc.contributor.authorPelletier, Alexandre
dc.contributor.authorGadaut, Johanna
dc.contributor.authorDavoine, Lindsay
dc.contributor.authorDupont, Cloé
dc.contributor.authorAmouyel, Philippe
dc.contributor.authorBonnefond, Amélie
dc.contributor.authorLafont, Frank
dc.contributor.authorAbdelfettah, Farida
dc.contributor.authorVerstreken, Patrik
dc.contributor.authorChapuis, Julien
dc.contributor.authorBarois, Nicolas
dc.contributor.authorDelahaye, Fabien
dc.contributor.authorDermaut, Bart
dc.contributor.authorLambert, Jean‑Charles
dc.contributor.authorCosta, Marcos Romualdo
dc.contributor.authorDourlen, Pierre
dc.date.accessioned2022-01-25T14:49:17Z
dc.date.available2022-01-25T14:49:17Z
dc.date.issued2022-01-08
dc.description.resumoThe 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 earlyendosome size deregulation, which is an early pathophysiological hallmark of AD pathologypt_BR
dc.identifier.citationLAMBERT, Erwan; SAHA, Orthis; LANDEIRA, Bruna Soares. FARIAS, Ana Raquel Melo de. 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 Romualdo. DOURLEN, Pierre. The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects. Acta Neuropathologica Communications, [S. l.], v. 10, n. 1, p. 4, jan. 2022. Doi: 10.1186/s40478-021-01285-5. Disponível em: https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01285-5. Acesso em: 25 jan. 2022.pt_BR
dc.identifier.doihttps://doi.org/10.1186/s40478-021-01285-5
dc.identifier.urihttps://repositorio.ufrn.br/handle/123456789/45713
dc.languageenpt_BR
dc.rightsAttribution 3.0 Brazil*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/br/*
dc.subjectBIN1 isoformspt_BR
dc.subjectNeurodegenerationpt_BR
dc.subjectEarly endosomept_BR
dc.subjectAlzheimer’s diseasept_BR
dc.subjectDrosophilapt_BR
dc.subjectHuman induced neuronspt_BR
dc.titleThe Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defectspt_BR
dc.typearticlept_BR

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