Neurotoxic reactive astrocytes induce cell death via saturated lipids

• Published in: Nature (London) Vol. 599; no. 7883; pp. 102 - 107
• Main Authors: Guttenplan, Kevin A., Weigel, Maya K., Prakash, Priya, Wijewardhane, Prageeth R., Hasel, Philip, Rufen-Blanchette, Uriel, Münch, Alexandra E., Blum, Jacob A., Fine, Jonathan, Neal, Mikaela C., Bruce, Kimberley D., Gitler, Aaron D., Chopra, Gaurav, Liddelow, Shane A., Barres, Ben A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-11-2021; Nature Publishing Group
• Subjects: 13/1; 13/2; 13/21; 13/51; 14/63; 631/378/1689/364; 631/378/2596/1308; 64/60; 82/58; Animals; Apolipoprotein E; Apoptosis; Astrocytes; Astrocytes - chemistry; Astrocytes - metabolism; Biocompatibility; Cell death; Cell Death - drug effects; Central nervous system; Chromatography; Culture Media, Conditioned - chemistry; Culture Media, Conditioned - toxicity; Endoplasmic reticulum; Enzymes; Fatty Acid Elongases - deficiency; Fatty Acid Elongases - genetics; Fatty Acid Elongases - metabolism; Female; Gene Knockout Techniques; Humanities and Social Sciences; Hypotheses; Kinases; Lipids; Lipids - chemistry; Lipids - toxicity; Lipoproteins; Male; Mass spectrometry; Membranes; Mice; Mice, Knockout; multidisciplinary; Nervous system; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurotoxicity; Neurotoxins - chemistry; Neurotoxins - toxicity; Proteins; Science; Science (multidisciplinary); Scientific imaging; Toxicity; Tumor necrosis factor-TNF
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03960-y

Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease
1
–
6
. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor
5
,
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.
Astrocytes can respond to diseases and injuries of the central nervous system by driving the death of neurons and mature oligodendrocytes through the delivery of long-chain saturated fatty acids contained in lipoparticles.