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; Ben A. Barres

doi:10.1038/s41586-021-03960-y

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, Ben A. Barres

Research output: Contribution to journal › Article › peer-review

320 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	102-107
Number of pages	6
Journal	Nature
Volume	599
Issue number	7883
DOIs	https://doi.org/10.1038/s41586-021-03960-y
State	Published - 4 Nov 2021
Externally published	Yes

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Guttenplan, K. A., Weigel, M. K., Prakash, P., Wijewardhane, P. R., Hasel, P., Rufen-Blanchette, U., Münch, A. E., Blum, J. A., Fine, J., Neal, M. C., Bruce, K. D., Gitler, A. D., Chopra, G., Liddelow, S. A., & Barres, B. A. (2021). Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature, 599(7883), 102-107. https://doi.org/10.1038/s41586-021-03960-y

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title = "Neurotoxic reactive astrocytes induce cell death via saturated lipids",

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.",

author = "Guttenplan, {Kevin A.} and Weigel, {Maya K.} and Priya Prakash and Wijewardhane, {Prageeth R.} and Philip Hasel and Uriel Rufen-Blanchette and M{\"u}nch, {Alexandra E.} and Blum, {Jacob A.} and Jonathan Fine and Neal, {Mikaela C.} and Bruce, {Kimberley D.} and Gitler, {Aaron D.} and Gaurav Chopra and Liddelow, {Shane A.} and Barres, {Ben A.}",

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doi = "10.1038/s41586-021-03960-y",

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T1 - Neurotoxic reactive astrocytes induce cell death via saturated lipids

AU - Guttenplan, Kevin A.

AU - Weigel, Maya K.

AU - Prakash, Priya

AU - Wijewardhane, Prageeth R.

AU - Hasel, Philip

AU - Rufen-Blanchette, Uriel

AU - Münch, Alexandra E.

AU - Blum, Jacob A.

AU - Fine, Jonathan

AU - Neal, Mikaela C.

AU - Bruce, Kimberley D.

AU - Gitler, Aaron D.

AU - Chopra, Gaurav

AU - Liddelow, Shane A.

AU - Barres, Ben A.

PY - 2021/11/4

Y1 - 2021/11/4

N2 - 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.

AB - 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.

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AN - SCOPUS:85116447845

SN - 0028-0836

VL - 599

SP - 102

EP - 107

JO - Nature

JF - Nature

IS - 7883

ER -

Neurotoxic reactive astrocytes induce cell death via saturated lipids

Abstract

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