16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro.

Autor: Sundberg M; Department of Neurology, F.M. Kirby Neurobiology Center, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Pinson H; Department of Physics and Center for Brains, Minds & Machines, MIT, Cambridge, MA, USA.; Applied Physics/Data Analytics, Vrije Universiteit Brussel, Brussels, Belgium., Smith RS; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Winden KD; Department of Neurology, F.M. Kirby Neurobiology Center, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Venugopal P; Department of Neurology, F.M. Kirby Neurobiology Center, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Tai DJC; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Gusella JF; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.; Program in Medical and Population Genetics Broad Institute of MIT and Harvard, Cambridge, MA, USA., Talkowski ME; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Walsh CA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Tegmark M; Department of Physics and Center for Brains, Minds & Machines, MIT, Cambridge, MA, USA., Sahin M; Department of Neurology, F.M. Kirby Neurobiology Center, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. mustafa.sahin@childrens.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 May 18; Vol. 12 (1), pp. 2897. Date of Electronic Publication: 2021 May 18.
DOI: 10.1038/s41467-021-23113-z
Abstrakt: Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.
Databáze: MEDLINE
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