TMEM106B regulates microglial proliferation and survival in response to demyelination

TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Science advances 2023-05, Vol.9 (18), p.eadd2676-eadd2676
Hauptverfasser: Zhang, Tingting, Pang, Weilun, Feng, Tuancheng, Guo, Jennifer, Wu, Kenton, Nunez Santos, Mariela, Arthanarisami, Akshayakeerthi, Nana, Alissa L, Nguyen, Quynh, Kim, Peter J, Jankowsky, Joanna L, Seeley, William W, Hu, Fenghua
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page eadd2676
container_issue 18
container_start_page eadd2676
container_title Science advances
container_volume 9
creator Zhang, Tingting
Pang, Weilun
Feng, Tuancheng
Guo, Jennifer
Wu, Kenton
Nunez Santos, Mariela
Arthanarisami, Akshayakeerthi
Nana, Alissa L
Nguyen, Quynh
Kim, Peter J
Jankowsky, Joanna L
Seeley, William W
Hu, Fenghua
description TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the risk allele is associated with myelin loss and decreased microglial numbers in humans. Collectively, our study unveils a previously unknown role of TMEM106B in promoting microglial functionality during demyelination.
doi_str_mv 10.1126/sciadv.add2676
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10162677</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2810915672</sourcerecordid><originalsourceid>FETCH-LOGICAL-c391t-389d1aeb9c67b62645cec0aa105de2ec025c9a9afa051c1aa9181e19820c0ce63</originalsourceid><addsrcrecordid>eNpVUU1LAzEQDaKoqFePskcvrZlsk92cRMUvULy05zDNTmsku6nJbsF_b7RV9DQP3pv3hnmMnQIfAwh1kazDZj3GphGqUjvsUJSVHAk5qXf_4AN2ktIb5xwmSknQ--ygrDIGyQ_ZbPp8-wxcXReRloPHnlLROhvD0jv0xSoG7xYUsXehK7BrijTEtVtnynV5Ja1Cl6joQ9FQ-0Hedd_KY7a3QJ_oZDuP2OzudnrzMHp6uX-8uXoa2VJDPypr3QDSXFtVzZVQE2nJckTgsiGRoZBWo8YFcgkWEDXUQKBrwS23pMojdrnxXQ3zlhpLXR_Rm1V0LcYPE9CZ_0znXs0yrA1wyHlVlR3Otw4xvA-UetO6ZMl77CgMyYgauAapKpGl4400fyelSIvfHODmqw-z6cNs-8gLZ3-v-5X_fL_8BGViimY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2810915672</pqid></control><display><type>article</type><title>TMEM106B regulates microglial proliferation and survival in response to demyelination</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Zhang, Tingting ; Pang, Weilun ; Feng, Tuancheng ; Guo, Jennifer ; Wu, Kenton ; Nunez Santos, Mariela ; Arthanarisami, Akshayakeerthi ; Nana, Alissa L ; Nguyen, Quynh ; Kim, Peter J ; Jankowsky, Joanna L ; Seeley, William W ; Hu, Fenghua</creator><creatorcontrib>Zhang, Tingting ; Pang, Weilun ; Feng, Tuancheng ; Guo, Jennifer ; Wu, Kenton ; Nunez Santos, Mariela ; Arthanarisami, Akshayakeerthi ; Nana, Alissa L ; Nguyen, Quynh ; Kim, Peter J ; Jankowsky, Joanna L ; Seeley, William W ; Hu, Fenghua</creatorcontrib><description>TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the risk allele is associated with myelin loss and decreased microglial numbers in humans. Collectively, our study unveils a previously unknown role of TMEM106B in promoting microglial functionality during demyelination.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.add2676</identifier><identifier>PMID: 37146150</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Brain - metabolism ; Cell Proliferation ; Demyelinating Diseases - genetics ; Demyelinating Diseases - metabolism ; Diseases and Disorders ; Humans ; Membrane Glycoproteins - metabolism ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mice, Knockout ; Microglia - metabolism ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Neuroscience ; Receptors, Immunologic - metabolism ; SciAdv r-articles</subject><ispartof>Science advances, 2023-05, Vol.9 (18), p.eadd2676-eadd2676</ispartof><rights>Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). 2023 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-389d1aeb9c67b62645cec0aa105de2ec025c9a9afa051c1aa9181e19820c0ce63</citedby><cites>FETCH-LOGICAL-c391t-389d1aeb9c67b62645cec0aa105de2ec025c9a9afa051c1aa9181e19820c0ce63</cites><orcidid>0000-0002-6447-9992 ; 0000-0003-1183-9920 ; 0000-0002-1740-5464 ; 0000-0003-1410-2027 ; 0000-0003-1676-9837</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10162677/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10162677/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37146150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Tingting</creatorcontrib><creatorcontrib>Pang, Weilun</creatorcontrib><creatorcontrib>Feng, Tuancheng</creatorcontrib><creatorcontrib>Guo, Jennifer</creatorcontrib><creatorcontrib>Wu, Kenton</creatorcontrib><creatorcontrib>Nunez Santos, Mariela</creatorcontrib><creatorcontrib>Arthanarisami, Akshayakeerthi</creatorcontrib><creatorcontrib>Nana, Alissa L</creatorcontrib><creatorcontrib>Nguyen, Quynh</creatorcontrib><creatorcontrib>Kim, Peter J</creatorcontrib><creatorcontrib>Jankowsky, Joanna L</creatorcontrib><creatorcontrib>Seeley, William W</creatorcontrib><creatorcontrib>Hu, Fenghua</creatorcontrib><title>TMEM106B regulates microglial proliferation and survival in response to demyelination</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the risk allele is associated with myelin loss and decreased microglial numbers in humans. Collectively, our study unveils a previously unknown role of TMEM106B in promoting microglial functionality during demyelination.</description><subject>Animals</subject><subject>Brain - metabolism</subject><subject>Cell Proliferation</subject><subject>Demyelinating Diseases - genetics</subject><subject>Demyelinating Diseases - metabolism</subject><subject>Diseases and Disorders</subject><subject>Humans</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microglia - metabolism</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neuroscience</subject><subject>Receptors, Immunologic - metabolism</subject><subject>SciAdv r-articles</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1LAzEQDaKoqFePskcvrZlsk92cRMUvULy05zDNTmsku6nJbsF_b7RV9DQP3pv3hnmMnQIfAwh1kazDZj3GphGqUjvsUJSVHAk5qXf_4AN2ktIb5xwmSknQ--ygrDIGyQ_ZbPp8-wxcXReRloPHnlLROhvD0jv0xSoG7xYUsXehK7BrijTEtVtnynV5Ja1Cl6joQ9FQ-0Hedd_KY7a3QJ_oZDuP2OzudnrzMHp6uX-8uXoa2VJDPypr3QDSXFtVzZVQE2nJckTgsiGRoZBWo8YFcgkWEDXUQKBrwS23pMojdrnxXQ3zlhpLXR_Rm1V0LcYPE9CZ_0znXs0yrA1wyHlVlR3Otw4xvA-UetO6ZMl77CgMyYgauAapKpGl4400fyelSIvfHODmqw-z6cNs-8gLZ3-v-5X_fL_8BGViimY</recordid><startdate>20230505</startdate><enddate>20230505</enddate><creator>Zhang, Tingting</creator><creator>Pang, Weilun</creator><creator>Feng, Tuancheng</creator><creator>Guo, Jennifer</creator><creator>Wu, Kenton</creator><creator>Nunez Santos, Mariela</creator><creator>Arthanarisami, Akshayakeerthi</creator><creator>Nana, Alissa L</creator><creator>Nguyen, Quynh</creator><creator>Kim, Peter J</creator><creator>Jankowsky, Joanna L</creator><creator>Seeley, William W</creator><creator>Hu, Fenghua</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6447-9992</orcidid><orcidid>https://orcid.org/0000-0003-1183-9920</orcidid><orcidid>https://orcid.org/0000-0002-1740-5464</orcidid><orcidid>https://orcid.org/0000-0003-1410-2027</orcidid><orcidid>https://orcid.org/0000-0003-1676-9837</orcidid></search><sort><creationdate>20230505</creationdate><title>TMEM106B regulates microglial proliferation and survival in response to demyelination</title><author>Zhang, Tingting ; Pang, Weilun ; Feng, Tuancheng ; Guo, Jennifer ; Wu, Kenton ; Nunez Santos, Mariela ; Arthanarisami, Akshayakeerthi ; Nana, Alissa L ; Nguyen, Quynh ; Kim, Peter J ; Jankowsky, Joanna L ; Seeley, William W ; Hu, Fenghua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-389d1aeb9c67b62645cec0aa105de2ec025c9a9afa051c1aa9181e19820c0ce63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Brain - metabolism</topic><topic>Cell Proliferation</topic><topic>Demyelinating Diseases - genetics</topic><topic>Demyelinating Diseases - metabolism</topic><topic>Diseases and Disorders</topic><topic>Humans</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microglia - metabolism</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Neuroscience</topic><topic>Receptors, Immunologic - metabolism</topic><topic>SciAdv r-articles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Tingting</creatorcontrib><creatorcontrib>Pang, Weilun</creatorcontrib><creatorcontrib>Feng, Tuancheng</creatorcontrib><creatorcontrib>Guo, Jennifer</creatorcontrib><creatorcontrib>Wu, Kenton</creatorcontrib><creatorcontrib>Nunez Santos, Mariela</creatorcontrib><creatorcontrib>Arthanarisami, Akshayakeerthi</creatorcontrib><creatorcontrib>Nana, Alissa L</creatorcontrib><creatorcontrib>Nguyen, Quynh</creatorcontrib><creatorcontrib>Kim, Peter J</creatorcontrib><creatorcontrib>Jankowsky, Joanna L</creatorcontrib><creatorcontrib>Seeley, William W</creatorcontrib><creatorcontrib>Hu, Fenghua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Tingting</au><au>Pang, Weilun</au><au>Feng, Tuancheng</au><au>Guo, Jennifer</au><au>Wu, Kenton</au><au>Nunez Santos, Mariela</au><au>Arthanarisami, Akshayakeerthi</au><au>Nana, Alissa L</au><au>Nguyen, Quynh</au><au>Kim, Peter J</au><au>Jankowsky, Joanna L</au><au>Seeley, William W</au><au>Hu, Fenghua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TMEM106B regulates microglial proliferation and survival in response to demyelination</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2023-05-05</date><risdate>2023</risdate><volume>9</volume><issue>18</issue><spage>eadd2676</spage><epage>eadd2676</epage><pages>eadd2676-eadd2676</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the risk allele is associated with myelin loss and decreased microglial numbers in humans. Collectively, our study unveils a previously unknown role of TMEM106B in promoting microglial functionality during demyelination.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>37146150</pmid><doi>10.1126/sciadv.add2676</doi><orcidid>https://orcid.org/0000-0002-6447-9992</orcidid><orcidid>https://orcid.org/0000-0003-1183-9920</orcidid><orcidid>https://orcid.org/0000-0002-1740-5464</orcidid><orcidid>https://orcid.org/0000-0003-1410-2027</orcidid><orcidid>https://orcid.org/0000-0003-1676-9837</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2375-2548
ispartof Science advances, 2023-05, Vol.9 (18), p.eadd2676-eadd2676
issn 2375-2548
2375-2548
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10162677
source MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Animals
Brain - metabolism
Cell Proliferation
Demyelinating Diseases - genetics
Demyelinating Diseases - metabolism
Diseases and Disorders
Humans
Membrane Glycoproteins - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
Microglia - metabolism
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neuroscience
Receptors, Immunologic - metabolism
SciAdv r-articles
title TMEM106B regulates microglial proliferation and survival in response to demyelination
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T23%3A34%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TMEM106B%20regulates%20microglial%20proliferation%20and%20survival%20in%20response%20to%20demyelination&rft.jtitle=Science%20advances&rft.au=Zhang,%20Tingting&rft.date=2023-05-05&rft.volume=9&rft.issue=18&rft.spage=eadd2676&rft.epage=eadd2676&rft.pages=eadd2676-eadd2676&rft.issn=2375-2548&rft.eissn=2375-2548&rft_id=info:doi/10.1126/sciadv.add2676&rft_dat=%3Cproquest_pubme%3E2810915672%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2810915672&rft_id=info:pmid/37146150&rfr_iscdi=true