The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs
- 1UCSF
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.
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BibTeX
@misc{lee2026functional,
title = {{The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs}},
author = {R. J. Lee and I. M. Rivas-Serna and E. K. Theisen and A. Bibo and E. B. Hardy and W. Cheng and Z. Zhou and J. S. Chavez-Rios and J. C. Forward and T. T. Pham and C. I. Thomas and A. Darehshouri and V. Mazurak and M. T. Clandinin and J. Vaughen},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754678},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754678v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs
AU - R. J. Lee
AU - I. M. Rivas-Serna
AU - E. K. Theisen
AU - A. Bibo
AU - E. B. Hardy
AU - W. Cheng
AU - Z. Zhou
AU - J. S. Chavez-Rios
AU - J. C. Forward
AU - T. T. Pham
AU - C. I. Thomas
AU - A. Darehshouri
AU - V. Mazurak
AU - M. T. Clandinin
AU - J. Vaughen
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754678
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754678v1
AB - 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.
ER -