Neurotoxic reactive astrocytes induce cell death via saturated lipids

Kevin A. Guttenplan, Maya K. Weigel, Priya Prakash, Prageeth R. Wijewardhane, Philip Hasel, Uriel Rufen-Blanchette, Alexandra E. Münch, Jacob A. Blum, Jonathan Fine, Mikaela C. Neal, Kimberley D. Bruce, Aaron D. Gitler, Gaurav Chopra, Shane A. Liddelow () and Ben A. Barres
Additional contact information
Kevin A. Guttenplan: Stanford University
Maya K. Weigel: Stanford University
Priya Prakash: Purdue University
Prageeth R. Wijewardhane: Purdue University
Philip Hasel: NYU School of Medicine
Uriel Rufen-Blanchette: NYU School of Medicine
Alexandra E. Münch: Stanford University
Jacob A. Blum: Stanford University
Jonathan Fine: Purdue University
Mikaela C. Neal: University of Colorado Anschutz Medical Campus
Kimberley D. Bruce: University of Colorado Anschutz Medical Campus
Aaron D. Gitler: Stanford University
Gaurav Chopra: Purdue University
Shane A. Liddelow: NYU School of Medicine
Ben A. Barres: Stanford University

Nature, 2021, vol. 599, issue 7883, 102-107

Abstract: Abstract Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease1–6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor5,6. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system.

Date: 2021
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DOI: 10.1038/s41586-021-03960-y

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