Neurotoxic reactive astrocytes induce cell death via saturated lipids
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...
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| Veröffentlicht in: | Nature (London) 2021-11, Vol.599 (7883), p.102-107 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1038/s41586-021-03960-y |
| format | Article |
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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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03960-y</identifier><identifier>PMID: 34616039</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>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</subject><ispartof>Nature (London), 2021-11, Vol.599 (7883), p.102-107</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>Copyright Nature Publishing Group Nov 4, 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c490t-c2b1fb6a173a06f7da921be45644717490f4a34a0d4425aff8f24cf748a9605b3</citedby><cites>FETCH-LOGICAL-c490t-c2b1fb6a173a06f7da921be45644717490f4a34a0d4425aff8f24cf748a9605b3</cites><orcidid>0000-0002-0840-1437 ; 0000-0003-0942-7898 ; 0000-0001-8603-1526 ; 0000-0003-4378-3685 ; 0000-0003-2193-9669 ; 0000-0003-4242-4349 ; 0000-0002-9781-3053 ; 0000-0002-9609-3277</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-03960-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-03960-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34616039$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guttenplan, Kevin A.</creatorcontrib><creatorcontrib>Weigel, Maya K.</creatorcontrib><creatorcontrib>Prakash, Priya</creatorcontrib><creatorcontrib>Wijewardhane, Prageeth R.</creatorcontrib><creatorcontrib>Hasel, Philip</creatorcontrib><creatorcontrib>Rufen-Blanchette, Uriel</creatorcontrib><creatorcontrib>Münch, Alexandra E.</creatorcontrib><creatorcontrib>Blum, Jacob A.</creatorcontrib><creatorcontrib>Fine, Jonathan</creatorcontrib><creatorcontrib>Neal, Mikaela C.</creatorcontrib><creatorcontrib>Bruce, Kimberley D.</creatorcontrib><creatorcontrib>Gitler, Aaron D.</creatorcontrib><creatorcontrib>Chopra, Gaurav</creatorcontrib><creatorcontrib>Liddelow, Shane A.</creatorcontrib><creatorcontrib>Barres, Ben A.</creatorcontrib><title>Neurotoxic reactive astrocytes induce cell death via saturated lipids</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>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.</description><subject>13/1</subject><subject>13/2</subject><subject>13/21</subject><subject>13/51</subject><subject>14/63</subject><subject>631/378/1689/364</subject><subject>631/378/2596/1308</subject><subject>64/60</subject><subject>82/58</subject><subject>Animals</subject><subject>Apolipoprotein E</subject><subject>Apoptosis</subject><subject>Astrocytes</subject><subject>Astrocytes - chemistry</subject><subject>Astrocytes - metabolism</subject><subject>Biocompatibility</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Central nervous system</subject><subject>Chromatography</subject><subject>Culture Media, Conditioned - chemistry</subject><subject>Culture Media, Conditioned - toxicity</subject><subject>Endoplasmic 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reactive astrocytes induce cell death via saturated lipids</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c490t-c2b1fb6a173a06f7da921be45644717490f4a34a0d4425aff8f24cf748a9605b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/1</topic><topic>13/2</topic><topic>13/21</topic><topic>13/51</topic><topic>14/63</topic><topic>631/378/1689/364</topic><topic>631/378/2596/1308</topic><topic>64/60</topic><topic>82/58</topic><topic>Animals</topic><topic>Apolipoprotein E</topic><topic>Apoptosis</topic><topic>Astrocytes</topic><topic>Astrocytes - 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Kimberley D.</au><au>Gitler, Aaron D.</au><au>Chopra, Gaurav</au><au>Liddelow, Shane A.</au><au>Barres, Ben A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neurotoxic reactive astrocytes induce cell death via saturated lipids</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-11-04</date><risdate>2021</risdate><volume>599</volume><issue>7883</issue><spage>102</spage><epage>107</epage><pages>102-107</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><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.
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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34616039</pmid><doi>10.1038/s41586-021-03960-y</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-0840-1437</orcidid><orcidid>https://orcid.org/0000-0003-0942-7898</orcidid><orcidid>https://orcid.org/0000-0001-8603-1526</orcidid><orcidid>https://orcid.org/0000-0003-4378-3685</orcidid><orcidid>https://orcid.org/0000-0003-2193-9669</orcidid><orcidid>https://orcid.org/0000-0003-4242-4349</orcidid><orcidid>https://orcid.org/0000-0002-9781-3053</orcidid><orcidid>https://orcid.org/0000-0002-9609-3277</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2021-11, Vol.599 (7883), p.102-107 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_journals_2594204489 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| 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 |
| title | Neurotoxic reactive astrocytes induce cell death via saturated lipids |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T13%3A36%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Neurotoxic%20reactive%20astrocytes%20induce%20cell%20death%20via%20saturated%20lipids&rft.jtitle=Nature%20(London)&rft.au=Guttenplan,%20Kevin%20A.&rft.date=2021-11-04&rft.volume=599&rft.issue=7883&rft.spage=102&rft.epage=107&rft.pages=102-107&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-021-03960-y&rft_dat=%3Cproquest_cross%3E2594204489%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2594204489&rft_id=info:pmid/34616039&rfr_iscdi=true |