| Autor: |
Saha, Orthis, Melo de Farias, Ana Raquel, 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. |
| Zdroj: |
Molecular Psychiatry; September 2024, Vol. 29 Issue: 9 p2634-2646, 13p |
| Abstrakt: |
Bridging 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 BIN1plays 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 BIN1wild type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), we show that BIN1is mainly expressed by oligodendrocytes and glutamatergic neurons, like in the human brain. Both BIN1HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1cell-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 BIN1plays 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. BIN1KO hiNs show reduced activity-dependent internalization and higher Cav1.2expression 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 BIN1KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1KO 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 progression. |
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