The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs

Authors

Lee, R. J., Rivas-Serna, I. M., Theisen, E. K., Bibo, A., Hardy, E. B., Cheng, W., Zhou, Z., Chavez-Rios, J. S., Forward, J. C., Pham, T. T., Thomas, C. I., Darehshouri, A., Mazurak, V., Clandinin, M. T., Vaughen, J.

Abstract

Neurons maintain specialized membranes necessary for lifelong circuit function. While neuronal membranes thus contain unique lipidomes, how and why specific lipids become synaptically enriched remains mysterious. Here, we identify a conserved hallmark of mature neurons, phosphatidylserines containing omega-3 fatty acids (n-3 PS), which dynamically accumulate during synaptogenesis from Drosophila to humans. This neuronal lipotype depends on dietary n-3 and lysosomal catabolism mediated by Saposin, the phospholipase PLA2G15, and the lysophospholipid transporter spin/SPNS1. Reducing neuronal PS biosynthesis by targeting the PS synthase (Pss) caused lipidomic, synaptic, and behavioral deficits exacerbated by impaired glycerophospholipid catabolism. While dietary, lysosomal, and lipoprotein manipulations broadly altered n-3 levels, silencing developmental activity-templating neurons selectively reduced n-3 PS. Remarkably, pathogenic Pss variants lacking feedback inhibition similarly reduced n-3 PS and impaired circuit function. As n-3 PS is reduced during neurodegeneration but absent from iPSC-derived neurons, important relationships between lipotype and physiology may not be recapitulated in vitro.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 02 Oct 2026.

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