Journal article
Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions
Neuron (Cambridge, Mass.), Vol.114(12), pp.2199-2220.e6
06/17/2026
DOI: 10.1016/j.neuron.2026.02.006
PMID: 41887214
Abstract
The complex morphologies of neurons and glia emerge through profound changes in membrane lipids and proteins during development. Lysosomes are central regulators of membrane remodeling, and mutations that affect lipid turnover in lysosomes are frequently associated with neurological disease. However, how these lysosomal functions might shape brain development remains incompletely understood. By analyzing lipid levels in the Drosophila brain, we discover transient increases in specific sphingolipids during development. This lipid bolus reflects biosynthetic inputs from both neurons and glia, and requires lysosomal catabolism for mature neuronal physiology to emerge. Remarkably, sphingolipid catabolism in glia is substantially driven by the phagolysosomal salvage of neuronal membranes to produce very long-chain ceramide phosphoethanolamine (CPE) lipids. CPE lipids are cell-autonomously required for glial autophagy and ramification into synaptic regions, and a genetic CPE biosensor localizes to infiltrated glial processes. Thus, developmentally regulated lysosomal activity obligately couples neuron-glia metabolic interactions to program dynamic glial morphogenesis.
Details
- Title: Subtitle
- Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions
- Creators
- Emma K Theisen - Stanford UniversityIrma Magaly Rivas-Serna - University of AlbertaPeiwen Cheng - University of California, San FranciscoRyan J Lee - Stanford UniversityConnon I Thomas - University of Colorado Anschutz Medical CampusAnza Darehshouri - University of Colorado Anschutz Medical CampusTaylor R Jay - Oregon Health & Science UniversityGovind Kunduri - National Cancer InstituteTasha T Nguyen - Stanford UniversityVera Mazurak - University of AlbertaM Thomas Clandinin - University of AlbertaThomas R Clandinin - Stanford UniversityJohn P Vaughen - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- Neuron (Cambridge, Mass.), Vol.114(12), pp.2199-2220.e6
- DOI
- 10.1016/j.neuron.2026.02.006
- PMID
- 41887214
- NLM abbreviation
- Neuron
- ISSN
- 0896-6273
- eISSN
- 1097-4199
- Publisher
- Cell Press; CAMBRIDGE
- Grant note
- Sandler PBBR Program Ludwig Family Foundation Simons Foundation NIH NINDS: R21 NS12458 NINDS: K99 NS133298 NIH: 1S10OD036258-01 Stanford Interdisciplinary Graduate Fellowship NCI, NIH, HHS Bloomington Drosophila Stock Center (NIH): P40OD018537 Harvard TRiP Center: R24 OD030002 Stanford Vision Core: P30EY026877
Research is conducted on Muwekma and Ramaytush Ohlone lands. We thank Clandinin and Vaughen lab members for discussions, and Estela Stevenson and Adriana Bibo for excellent assistance. We thank Michael Hoch, Tobi Stork, Jaeda Coutinho-Budd, Liqun Luo, Jairaj Acharya, and Colleen McLaughlin for discussion and sharing flies, and Rushika Perera, Andrew Yang, and Leanne Jones for confocal access. Funding by Sandler PBBR Program (J.P.V.), Ludwig Family Foundation (T.R.C.), Simons Foundation (T.R.C.), NIH NINDS R21 NS12458 (T.R.C.), NINDS K99 NS133298 (T.R.J.), NIH grant 1S10OD036258-01 (A.D.), and Stanford Interdisciplinary Graduate Fellowship (E.K.T.). G.K. is supported by the intramural division of the NCI, NIH, HHS. We gratefully acknowledge the Bloomington Drosophila Stock Center (NIH P40OD018537), the Harvard TRiP Center (R24 OD030002), and the Stanford Vision Core (P30EY026877).
- Language
- English
- Electronic publication date
- 03/25/2026
- Date published
- 06/17/2026
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9985149085602771
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