The Alzheimer’s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons

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dc.contributor.authorSaha, Orthis
dc.contributor.authorFarias, Ana Raquel Melo de
dc.contributor.authorPelletier, Alexandre
dc.contributor.authorSiedlecki-Wullich, Dolores
dc.contributor.authorLandeira, Bruna Soares
dc.contributor.authorGadaut, Johanna
dc.contributor.authorCarrier, Arnaud
dc.contributor.authorVreulx, Anaïs-Camille
dc.contributor.authorGuyot, Karine
dc.contributor.authorShen, Yun
dc.contributor.authorBonnefond, Amelie
dc.contributor.authorAmouyel, Philippe
dc.contributor.authorTcw, Julia
dc.contributor.authorKilinc, Devrim
dc.contributor.authorQueiroz, Claudio Marcos Teixeira de
dc.contributor.authorDelahaye, Fabien
dc.contributor.authorLambert, Jean-Charles
dc.contributor.authorCosta, Marcos Romualdo
dc.date.accessioned2024-07-02T16:20:24Z
dc.date.available2024-07-02T16:20:24Z
dc.date.issued2024-03
dc.description.resumoBridging Integrator 1 (BIN1) is the second most important Alzheimer’s disease (AD) risk gene, but its physiological roles in neurons and its contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role in the regulation of calcium homeostasis, electrical activity, and gene expression of glutamatergic neurons. Using single-cell RNA-sequencing on cerebral organoids generated from isogenic BIN1 wild type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), we show that BIN1 is mainly expressed by oligodendrocytes and glutamatergic neurons, like in the human brain. Both BIN1 HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1 cell-autonomously regulates gene expression in glutamatergic neurons by using a novel protocol to generate pure culture of hiPSC-derived induced neurons (hiNs). Using this system, we also show that BIN1 plays a key role in the regulation of neuronal calcium transients and electrical activity via its interaction with the L-type voltage-gated calcium channel Cav1.2. BIN1 KO hiNs show reduced activity-dependent internalization and higher Cav1.2 expression compared to WT hiNs. Pharmacological blocking of this channel with clinically relevant doses of nifedipine, a calcium channel blocker, partly rescues electrical and gene expression alterations in BIN1 KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1 KO hiNs that affect biological processes related to calcium homeostasis are also present in glutamatergic neurons of the human brain at late stages of AD pathology. Together, these findings suggest that BIN1-dependent alterations in neuronal properties could contribute to AD pathophysiology and that treatment with low doses of clinically approved calcium blockers should be considered as an option to slow disease-onset and progressionpt_BR
dc.identifier.citationSAHA, Orthis; FARIAS, Ana Raquel Melo de; PELLETIER, Alexandre; SIEDLECKI-WULLICH, Dolores; LANDEIRA, Bruna Soares; GADAUT, Johanna; CARRIER, Arnaud; VREULX, Anaïs-Camille; GUYOT, Karine; SHEN, Yun; BONNEFOND, Amelie; AMOUYEL, Philippe; TCW, Julia; KILINC, Devrim; QUEIROZ, Claudio Marcos; DELAHAYE, Fabien; LAMBERT, Jean-Charles; COSTA, Marcos R. The Alzheimer’s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons. Molecular Psychiatry, [S. l.], mar. 2024. Doi: http://dx.doi.org/10.1038/s41380-024-02502-y. Disponível em: https://www.nature.com/articles/s41380-024-02502-y. Acesso em: 02 jul. 2024pt_BR
dc.identifier.doi10.1038/s41380-024-02502-y
dc.identifier.urihttps://repositorio.ufrn.br/handle/123456789/58532
dc.languageenpt_BR
dc.publisherSpringer Science and Business Media LLCpt_BR
dc.rightsAttribution 3.0 Brazil*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/br/*
dc.subjectAlzheimer diseasept_BR
dc.subjectBridging Integrator 1 (BIN1)pt_BR
dc.subjectSingle-cell gene expression analysispt_BR
dc.titleThe Alzheimer’s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neuronspt_BR
dc.typearticlept_BR

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