16pdel lipid changes in iPSC-derived neurons and function of FAM57B in lipid metabolism and synaptogenesis
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Published version
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5.72 MB
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Author(s)
Tomasello, Danielle L
Kim, Jiyoon L
Khodour, Yara
McCammon, Jasmine M
Mitalipova, Maya
Jaenisch, Rudolf
Futerman, Anthony H
Sive, Hazel
Date Issued
2022
Journal
iScience
Publisher
Elsevier BV
Citation
Tomasello, Danielle L, Kim, Jiyoon L, Khodour, Yara, McCammon, Jasmine M, Mitalipova, Maya et al. 2022. "16pdel lipid changes in iPSC-derived neurons and function of FAM57B in lipid metabolism and synaptogenesis." iScience, 25 (1).
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.ISCI.2021.103551
