16pdel lipid changes in iPSC-derived neurons and function of FAM57B in lipid metabolism and synaptogenesis.

Autor:	Tomasello DL; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Kim JL; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel., Khodour Y; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel., McCammon JM; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Mitalipova M; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Jaenisch R; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Futerman AH; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel., Sive H; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2021 Dec 02; Vol. 25 (1), pp. 103551. Date of Electronic Publication: 2021 Dec 02 (Print Publication: 2022).
DOI:	10.1016/j.isci.2021.103551
Abstrakt:	The complex 16p11.2 deletion syndrome (16pdel) is accompanied by neurological disorders, including epilepsy, autism spectrum disorder, and intellectual disability. We demonstrated that 16pdel iPSC differentiated neurons from affected people show augmented local field potential activity and altered ceramide-related lipid species relative to unaffected. FAM57B , a poorly characterized gene in the 16p11.2 interval, has emerged as a candidate tied to symptomatology. We found that FAM57B modulates ceramide synthase (CerS) activity, but is not a CerS per se. In FAM57B mutant human neuronal cells and zebrafish brain, composition and levels of sphingolipids and glycerolipids associated with cellular membranes are disrupted. Consistently, we observed aberrant plasma membrane architecture and synaptic protein mislocalization, which were accompanied by depressed brain and behavioral activity. Together, these results suggest that haploinsufficiency of FAM57B contributes to changes in neuronal activity and function in 16pdel syndrome through a crucial role for the gene in lipid metabolism. Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. (© 2021 The Author(s).)
Databáze:	MEDLINE
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