Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits
Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was sig...
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| Veröffentlicht in: | Cell biology and toxicology 2022-04, Vol.38 (2), p.347-369 |
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| creator | Zhang, Lei Cheng, Yanyong Xue, Zhenyu Li, Jingjie Wu, Niming Yan, Jia Wang, Jie Wang, Chao Chen, Weidong Zhou, Tao Qiu, Zilong Jiang, Hong |
| description | Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was significantly downregulated in the prefrontal cortex of young mice after multiple sevoflurane anesthesia exposures. Importantly, sevoflurane led to a decrease in protein synthesis in mouse cortical neurons that was fully rescued by YTHDF1, suggesting that anesthesia may affect early brain development by affecting m6A-dependent mRNA translation. Transcriptome-wide experiments showed that numerous mRNA targets related to synaptic functions in the prefrontal mouse cortex were associated with m6A methylation and YTHDF1. In particular, we found that synaptophysin, a critical presynaptic protein, was specifically modified by m6A methylation and associated with YTHDF1, and m6A methylation of synaptophysin decreased with multiple sevoflurane exposures. Importantly, we showed that fine motor control skills and cognitive functions were impaired in mice with multiple anesthesia exposures, and these effects were fully reversed by reintroducing YTHDF1 through a blood-brain barrier (BBB)-crossing viral delivery system. Finally, we found that the fine motor skills in children who underwent prolonged anesthesia were compromised 6 months after surgery. Our findings indicated that impairment in the translational regulation of mRNA via N6-methyladenosine methylation is a potential mechanism underlying the effects of anesthesia on neural development in the young brain.
Graphical abstract
1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity.
2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice.
3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice. |
| doi_str_mv | 10.1007/s10565-021-09601-4 |
| format | Article |
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Graphical abstract
1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity.
2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice.
3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.</description><identifier>ISSN: 0742-2091</identifier><identifier>EISSN: 1573-6822</identifier><identifier>DOI: 10.1007/s10565-021-09601-4</identifier><identifier>PMID: 33928466</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Adenosine - genetics ; Adenosine - metabolism ; Anesthesia ; Animals ; Biochemistry ; Biomedical and Life Sciences ; Blood-brain barrier ; Cell Biology ; Children ; Cognition ; Cognitive ability ; Exposure ; Homology ; Life Sciences ; Methylation ; Mice ; Motor skill ; Motor task performance ; N6-methyladenosine ; Original Article ; Pharmacology/Toxicology ; Prefrontal cortex ; Protein Biosynthesis ; Protein synthesis ; Proteins ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Sevoflurane ; Sevoflurane - adverse effects ; Synaptophysin ; Synaptophysin - genetics ; Synaptophysin - metabolism ; Transcriptomes ; Translation</subject><ispartof>Cell biology and toxicology, 2022-04, Vol.38 (2), p.347-369</ispartof><rights>The Author(s), under exclusive licence to Springer Nature B.V. 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature B.V.</rights><rights>The Author(s), under exclusive licence to Springer Nature B.V. 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-e85df392876a8175a5f356724686b5155e21780f5785fb94939e4ca9f770c7e63</citedby><cites>FETCH-LOGICAL-c375t-e85df392876a8175a5f356724686b5155e21780f5785fb94939e4ca9f770c7e63</cites><orcidid>0000-0001-7188-5713</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10565-021-09601-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10565-021-09601-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33928466$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Cheng, Yanyong</creatorcontrib><creatorcontrib>Xue, Zhenyu</creatorcontrib><creatorcontrib>Li, Jingjie</creatorcontrib><creatorcontrib>Wu, Niming</creatorcontrib><creatorcontrib>Yan, Jia</creatorcontrib><creatorcontrib>Wang, Jie</creatorcontrib><creatorcontrib>Wang, Chao</creatorcontrib><creatorcontrib>Chen, Weidong</creatorcontrib><creatorcontrib>Zhou, Tao</creatorcontrib><creatorcontrib>Qiu, Zilong</creatorcontrib><creatorcontrib>Jiang, Hong</creatorcontrib><title>Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits</title><title>Cell biology and toxicology</title><addtitle>Cell Biol Toxicol</addtitle><addtitle>Cell Biol Toxicol</addtitle><description>Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was significantly downregulated in the prefrontal cortex of young mice after multiple sevoflurane anesthesia exposures. Importantly, sevoflurane led to a decrease in protein synthesis in mouse cortical neurons that was fully rescued by YTHDF1, suggesting that anesthesia may affect early brain development by affecting m6A-dependent mRNA translation. Transcriptome-wide experiments showed that numerous mRNA targets related to synaptic functions in the prefrontal mouse cortex were associated with m6A methylation and YTHDF1. In particular, we found that synaptophysin, a critical presynaptic protein, was specifically modified by m6A methylation and associated with YTHDF1, and m6A methylation of synaptophysin decreased with multiple sevoflurane exposures. Importantly, we showed that fine motor control skills and cognitive functions were impaired in mice with multiple anesthesia exposures, and these effects were fully reversed by reintroducing YTHDF1 through a blood-brain barrier (BBB)-crossing viral delivery system. Finally, we found that the fine motor skills in children who underwent prolonged anesthesia were compromised 6 months after surgery. Our findings indicated that impairment in the translational regulation of mRNA via N6-methyladenosine methylation is a potential mechanism underlying the effects of anesthesia on neural development in the young brain.
Graphical abstract
1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity.
2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice.
3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.</description><subject>Adenosine - genetics</subject><subject>Adenosine - metabolism</subject><subject>Anesthesia</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Blood-brain barrier</subject><subject>Cell Biology</subject><subject>Children</subject><subject>Cognition</subject><subject>Cognitive ability</subject><subject>Exposure</subject><subject>Homology</subject><subject>Life Sciences</subject><subject>Methylation</subject><subject>Mice</subject><subject>Motor skill</subject><subject>Motor task performance</subject><subject>N6-methyladenosine</subject><subject>Original Article</subject><subject>Pharmacology/Toxicology</subject><subject>Prefrontal cortex</subject><subject>Protein Biosynthesis</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Sevoflurane</subject><subject>Sevoflurane - adverse effects</subject><subject>Synaptophysin</subject><subject>Synaptophysin - genetics</subject><subject>Synaptophysin - 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impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits</title><author>Zhang, Lei ; Cheng, Yanyong ; Xue, Zhenyu ; Li, Jingjie ; Wu, Niming ; Yan, Jia ; Wang, Jie ; Wang, Chao ; Chen, Weidong ; Zhou, Tao ; Qiu, Zilong ; Jiang, Hong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-e85df392876a8175a5f356724686b5155e21780f5785fb94939e4ca9f770c7e63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adenosine - genetics</topic><topic>Adenosine - metabolism</topic><topic>Anesthesia</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Blood-brain barrier</topic><topic>Cell Biology</topic><topic>Children</topic><topic>Cognition</topic><topic>Cognitive ability</topic><topic>Exposure</topic><topic>Homology</topic><topic>Life Sciences</topic><topic>Methylation</topic><topic>Mice</topic><topic>Motor skill</topic><topic>Motor task performance</topic><topic>N6-methyladenosine</topic><topic>Original Article</topic><topic>Pharmacology/Toxicology</topic><topic>Prefrontal cortex</topic><topic>Protein Biosynthesis</topic><topic>Protein synthesis</topic><topic>Proteins</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Sevoflurane</topic><topic>Sevoflurane - adverse effects</topic><topic>Synaptophysin</topic><topic>Synaptophysin - genetics</topic><topic>Synaptophysin - metabolism</topic><topic>Transcriptomes</topic><topic>Translation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Cheng, Yanyong</creatorcontrib><creatorcontrib>Xue, Zhenyu</creatorcontrib><creatorcontrib>Li, Jingjie</creatorcontrib><creatorcontrib>Wu, Niming</creatorcontrib><creatorcontrib>Yan, Jia</creatorcontrib><creatorcontrib>Wang, Jie</creatorcontrib><creatorcontrib>Wang, 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Edition</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Cell biology and toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Lei</au><au>Cheng, Yanyong</au><au>Xue, Zhenyu</au><au>Li, Jingjie</au><au>Wu, Niming</au><au>Yan, Jia</au><au>Wang, Jie</au><au>Wang, Chao</au><au>Chen, Weidong</au><au>Zhou, Tao</au><au>Qiu, Zilong</au><au>Jiang, Hong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits</atitle><jtitle>Cell biology and toxicology</jtitle><stitle>Cell Biol Toxicol</stitle><addtitle>Cell Biol Toxicol</addtitle><date>2022-04-01</date><risdate>2022</risdate><volume>38</volume><issue>2</issue><spage>347</spage><epage>369</epage><pages>347-369</pages><issn>0742-2091</issn><eissn>1573-6822</eissn><abstract>Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was significantly downregulated in the prefrontal cortex of young mice after multiple sevoflurane anesthesia exposures. Importantly, sevoflurane led to a decrease in protein synthesis in mouse cortical neurons that was fully rescued by YTHDF1, suggesting that anesthesia may affect early brain development by affecting m6A-dependent mRNA translation. Transcriptome-wide experiments showed that numerous mRNA targets related to synaptic functions in the prefrontal mouse cortex were associated with m6A methylation and YTHDF1. In particular, we found that synaptophysin, a critical presynaptic protein, was specifically modified by m6A methylation and associated with YTHDF1, and m6A methylation of synaptophysin decreased with multiple sevoflurane exposures. Importantly, we showed that fine motor control skills and cognitive functions were impaired in mice with multiple anesthesia exposures, and these effects were fully reversed by reintroducing YTHDF1 through a blood-brain barrier (BBB)-crossing viral delivery system. Finally, we found that the fine motor skills in children who underwent prolonged anesthesia were compromised 6 months after surgery. Our findings indicated that impairment in the translational regulation of mRNA via N6-methyladenosine methylation is a potential mechanism underlying the effects of anesthesia on neural development in the young brain.
Graphical abstract
1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity.
2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice.
3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>33928466</pmid><doi>10.1007/s10565-021-09601-4</doi><tpages>23</tpages><orcidid>https://orcid.org/0000-0001-7188-5713</orcidid></addata></record> |
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| ispartof | Cell biology and toxicology, 2022-04, Vol.38 (2), p.347-369 |
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| language | eng |
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| subjects | Adenosine - genetics Adenosine - metabolism Anesthesia Animals Biochemistry Biomedical and Life Sciences Blood-brain barrier Cell Biology Children Cognition Cognitive ability Exposure Homology Life Sciences Methylation Mice Motor skill Motor task performance N6-methyladenosine Original Article Pharmacology/Toxicology Prefrontal cortex Protein Biosynthesis Protein synthesis Proteins RNA, Messenger - genetics RNA, Messenger - metabolism Sevoflurane Sevoflurane - adverse effects Synaptophysin Synaptophysin - genetics Synaptophysin - metabolism Transcriptomes Translation |
| title | Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits |
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