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

Nature. 2021 Nov;599(7883):102-107. doi: 10.1038/s41586-021-03960-y. Epub 2021 Oct 6.

Authors

Kevin A Guttenplan^{1

2}, Maya K Weigel^#¹, Priya Prakash^#³, Prageeth R Wijewardhane³, Philip Hasel⁴, Uriel Rufen-Blanchette⁴, Alexandra E Münch¹, Jacob A Blum², Jonathan Fine³, Mikaela C Neal⁵, Kimberley D Bruce⁵, Aaron D Gitler², Gaurav Chopra^{3

6

7

8

9}, Shane A Liddelow^{10

11

12

13}, Ben A Barres¹

Affiliations

¹ Department of Neurobiology, Stanford University, Stanford, CA, USA.
² Department of Genetics, Stanford University, Stanford, CA, USA.
³ Department of Chemistry, Purdue University, West Lafayette, IN, USA.
⁴ Neuroscience Institute, NYU School of Medicine, New York, NY, USA.
⁵ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁶ Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, USA.
⁷ Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA.
⁸ Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
⁹ Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN, USA.
¹⁰ Neuroscience Institute, NYU School of Medicine, New York, NY, USA. [email protected].
¹¹ Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA. [email protected].
¹² Department of Ophthalmology, NYU School of Medicine, New York, NY, USA. [email protected].
¹³ The Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA. [email protected].

^# Contributed equally.

PMID: 34616039
DOI: 10.1038/s41586-021-03960-y

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Astrocytes / chemistry*
Astrocytes / metabolism*
Cell Death / drug effects*
Culture Media, Conditioned / chemistry
Culture Media, Conditioned / toxicity
Fatty Acid Elongases / deficiency
Fatty Acid Elongases / genetics
Fatty Acid Elongases / metabolism
Female
Gene Knockout Techniques
Lipids / chemistry*
Lipids / toxicity*
Male
Mice
Mice, Knockout
Neurodegenerative Diseases / metabolism
Neurodegenerative Diseases / pathology
Neurotoxins / chemistry
Neurotoxins / toxicity

Substances

Culture Media, Conditioned
Elovl1 protein, mouse
Lipids
Neurotoxins
Fatty Acid Elongases

Abstract

Publication types

MeSH terms

Substances

Grants and funding