Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology
Introduction The cytoprotective PTEN‐induced kinase 1 (PINK1)‐parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways...
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| Veröffentlicht in: | Alzheimer's & dementia 2021-03, Vol.17 (3), p.417-430 |
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| creator | Hou, Xu Watzlawik, Jens O. Cook, Casey Liu, Chia‐Chen Kang, Silvia S. Lin, Wen‐Lang DeTure, Michael Heckman, Michael G. Diehl, Nancy N. Al‐Shaikh, Fadi S. Hanna Walton, Ronald L. Ross, Owen A. Melrose, Heather L. Ertekin‐Taner, Nilüfer Bu, Guojun Petrucelli, Leonard Fryer, John D. Murray, Melissa E. Dickson, Dennis W. Fiesel, Fabienne C. Springer, Wolfdieter |
| description | Introduction
The cytoprotective PTEN‐induced kinase 1 (PINK1)‐parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis.
Methods
Morphology, levels, and distribution of the mitophagy tag pS65‐Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models.
Results
Analyses revealed significant increases of pS65‐Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho‐tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co‐localization of pS65‐Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed.
Discussion
Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease. |
| doi_str_mv | 10.1002/alz.12198 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8048674</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2453689406</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4158-291345b3d3983a2ce4b42cac139da48221a633967c784813d765e7f24863b02a3</originalsourceid><addsrcrecordid>eNp1kU1v1DAQhi0EoqVw4A8g36CHbf2VxL4grSpKK23VC1y4WLPObGLkjRfbaZX-egK7rODAYTQjzaNnRnoJecvZBWdMXEJ4uuCCG_2MnPKqEotKNOb5ca7ZCXmV83fGFNO8eklOpGSG1YafkvHOl7jroZsohIIJio9Dpn6gy_DUo99iep9p6zNCRgpprpyj81CwpY--9LRLMIwhPoAbY4BEW-xwOIgoDC1FSGGiBUa6g9LHELvpNXmxgZDxzaGfka_Xn75c3SxW959vr5arhVO80gthuFTVWrbSaAnCoVor4cBxaVpQWggOtZSmblyjleaybeoKm41QupZrJkCekY97725cb7F1OJQEwe6S30KabARv_90MvrddfLCazY5GzYIPB0GKP0bMxW59dhgCDBjHbIWqZK2NYvWMnu9Rl2LOCTfHM5zZXzHZOSb7O6aZfff3X0fyTy4zcLkHHn3A6f8mu1x92yt_Ap3hnxc</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2453689406</pqid></control><display><type>article</type><title>Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology</title><source>Access via Wiley Online Library</source><creator>Hou, Xu ; Watzlawik, Jens O. ; Cook, Casey ; Liu, Chia‐Chen ; Kang, Silvia S. ; Lin, Wen‐Lang ; DeTure, Michael ; Heckman, Michael G. ; Diehl, Nancy N. ; Al‐Shaikh, Fadi S. Hanna ; Walton, Ronald L. ; Ross, Owen A. ; Melrose, Heather L. ; Ertekin‐Taner, Nilüfer ; Bu, Guojun ; Petrucelli, Leonard ; Fryer, John D. ; Murray, Melissa E. ; Dickson, Dennis W. ; Fiesel, Fabienne C. ; Springer, Wolfdieter</creator><creatorcontrib>Hou, Xu ; Watzlawik, Jens O. ; Cook, Casey ; Liu, Chia‐Chen ; Kang, Silvia S. ; Lin, Wen‐Lang ; DeTure, Michael ; Heckman, Michael G. ; Diehl, Nancy N. ; Al‐Shaikh, Fadi S. Hanna ; Walton, Ronald L. ; Ross, Owen A. ; Melrose, Heather L. ; Ertekin‐Taner, Nilüfer ; Bu, Guojun ; Petrucelli, Leonard ; Fryer, John D. ; Murray, Melissa E. ; Dickson, Dennis W. ; Fiesel, Fabienne C. ; Springer, Wolfdieter</creatorcontrib><description>Introduction
The cytoprotective PTEN‐induced kinase 1 (PINK1)‐parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis.
Methods
Morphology, levels, and distribution of the mitophagy tag pS65‐Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models.
Results
Analyses revealed significant increases of pS65‐Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho‐tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co‐localization of pS65‐Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed.
Discussion
Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.</description><identifier>ISSN: 1552-5260</identifier><identifier>EISSN: 1552-5279</identifier><identifier>DOI: 10.1002/alz.12198</identifier><identifier>PMID: 33090691</identifier><language>eng</language><publisher>United States: John Wiley and Sons Inc</publisher><subject>Alzheimer's disease ; autophagy ; granulovacuolar degeneration ; lysosomes ; mitochondria ; mitophagy ; Parkin ; PINK1 ; PRKN ; tau ; ubiquitin</subject><ispartof>Alzheimer's & dementia, 2021-03, Vol.17 (3), p.417-430</ispartof><rights>2020 The Authors. published by Wiley Periodicals LLC on behalf of Alzheimer's Association.</rights><rights>2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4158-291345b3d3983a2ce4b42cac139da48221a633967c784813d765e7f24863b02a3</citedby><cites>FETCH-LOGICAL-c4158-291345b3d3983a2ce4b42cac139da48221a633967c784813d765e7f24863b02a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Falz.12198$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Falz.12198$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33090691$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hou, Xu</creatorcontrib><creatorcontrib>Watzlawik, Jens O.</creatorcontrib><creatorcontrib>Cook, Casey</creatorcontrib><creatorcontrib>Liu, Chia‐Chen</creatorcontrib><creatorcontrib>Kang, Silvia S.</creatorcontrib><creatorcontrib>Lin, Wen‐Lang</creatorcontrib><creatorcontrib>DeTure, Michael</creatorcontrib><creatorcontrib>Heckman, Michael G.</creatorcontrib><creatorcontrib>Diehl, Nancy N.</creatorcontrib><creatorcontrib>Al‐Shaikh, Fadi S. Hanna</creatorcontrib><creatorcontrib>Walton, Ronald L.</creatorcontrib><creatorcontrib>Ross, Owen A.</creatorcontrib><creatorcontrib>Melrose, Heather L.</creatorcontrib><creatorcontrib>Ertekin‐Taner, Nilüfer</creatorcontrib><creatorcontrib>Bu, Guojun</creatorcontrib><creatorcontrib>Petrucelli, Leonard</creatorcontrib><creatorcontrib>Fryer, John D.</creatorcontrib><creatorcontrib>Murray, Melissa E.</creatorcontrib><creatorcontrib>Dickson, Dennis W.</creatorcontrib><creatorcontrib>Fiesel, Fabienne C.</creatorcontrib><creatorcontrib>Springer, Wolfdieter</creatorcontrib><title>Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology</title><title>Alzheimer's & dementia</title><addtitle>Alzheimers Dement</addtitle><description>Introduction
The cytoprotective PTEN‐induced kinase 1 (PINK1)‐parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis.
Methods
Morphology, levels, and distribution of the mitophagy tag pS65‐Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models.
Results
Analyses revealed significant increases of pS65‐Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho‐tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co‐localization of pS65‐Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed.
Discussion
Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.</description><subject>Alzheimer's disease</subject><subject>autophagy</subject><subject>granulovacuolar degeneration</subject><subject>lysosomes</subject><subject>mitochondria</subject><subject>mitophagy</subject><subject>Parkin</subject><subject>PINK1</subject><subject>PRKN</subject><subject>tau</subject><subject>ubiquitin</subject><issn>1552-5260</issn><issn>1552-5279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1kU1v1DAQhi0EoqVw4A8g36CHbf2VxL4grSpKK23VC1y4WLPObGLkjRfbaZX-egK7rODAYTQjzaNnRnoJecvZBWdMXEJ4uuCCG_2MnPKqEotKNOb5ca7ZCXmV83fGFNO8eklOpGSG1YafkvHOl7jroZsohIIJio9Dpn6gy_DUo99iep9p6zNCRgpprpyj81CwpY--9LRLMIwhPoAbY4BEW-xwOIgoDC1FSGGiBUa6g9LHELvpNXmxgZDxzaGfka_Xn75c3SxW959vr5arhVO80gthuFTVWrbSaAnCoVor4cBxaVpQWggOtZSmblyjleaybeoKm41QupZrJkCekY97725cb7F1OJQEwe6S30KabARv_90MvrddfLCazY5GzYIPB0GKP0bMxW59dhgCDBjHbIWqZK2NYvWMnu9Rl2LOCTfHM5zZXzHZOSb7O6aZfff3X0fyTy4zcLkHHn3A6f8mu1x92yt_Ap3hnxc</recordid><startdate>202103</startdate><enddate>202103</enddate><creator>Hou, Xu</creator><creator>Watzlawik, Jens O.</creator><creator>Cook, Casey</creator><creator>Liu, Chia‐Chen</creator><creator>Kang, Silvia S.</creator><creator>Lin, Wen‐Lang</creator><creator>DeTure, Michael</creator><creator>Heckman, Michael G.</creator><creator>Diehl, Nancy N.</creator><creator>Al‐Shaikh, Fadi S. Hanna</creator><creator>Walton, Ronald L.</creator><creator>Ross, Owen A.</creator><creator>Melrose, Heather L.</creator><creator>Ertekin‐Taner, Nilüfer</creator><creator>Bu, Guojun</creator><creator>Petrucelli, Leonard</creator><creator>Fryer, John D.</creator><creator>Murray, Melissa E.</creator><creator>Dickson, Dennis W.</creator><creator>Fiesel, Fabienne C.</creator><creator>Springer, Wolfdieter</creator><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202103</creationdate><title>Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology</title><author>Hou, Xu ; Watzlawik, Jens O. ; Cook, Casey ; Liu, Chia‐Chen ; Kang, Silvia S. ; Lin, Wen‐Lang ; DeTure, Michael ; Heckman, Michael G. ; Diehl, Nancy N. ; Al‐Shaikh, Fadi S. Hanna ; Walton, Ronald L. ; Ross, Owen A. ; Melrose, Heather L. ; Ertekin‐Taner, Nilüfer ; Bu, Guojun ; Petrucelli, Leonard ; Fryer, John D. ; Murray, Melissa E. ; Dickson, Dennis W. ; Fiesel, Fabienne C. ; Springer, Wolfdieter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4158-291345b3d3983a2ce4b42cac139da48221a633967c784813d765e7f24863b02a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alzheimer's disease</topic><topic>autophagy</topic><topic>granulovacuolar degeneration</topic><topic>lysosomes</topic><topic>mitochondria</topic><topic>mitophagy</topic><topic>Parkin</topic><topic>PINK1</topic><topic>PRKN</topic><topic>tau</topic><topic>ubiquitin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hou, Xu</creatorcontrib><creatorcontrib>Watzlawik, Jens O.</creatorcontrib><creatorcontrib>Cook, Casey</creatorcontrib><creatorcontrib>Liu, Chia‐Chen</creatorcontrib><creatorcontrib>Kang, Silvia S.</creatorcontrib><creatorcontrib>Lin, Wen‐Lang</creatorcontrib><creatorcontrib>DeTure, Michael</creatorcontrib><creatorcontrib>Heckman, Michael G.</creatorcontrib><creatorcontrib>Diehl, Nancy N.</creatorcontrib><creatorcontrib>Al‐Shaikh, Fadi S. Hanna</creatorcontrib><creatorcontrib>Walton, Ronald L.</creatorcontrib><creatorcontrib>Ross, Owen A.</creatorcontrib><creatorcontrib>Melrose, Heather L.</creatorcontrib><creatorcontrib>Ertekin‐Taner, Nilüfer</creatorcontrib><creatorcontrib>Bu, Guojun</creatorcontrib><creatorcontrib>Petrucelli, Leonard</creatorcontrib><creatorcontrib>Fryer, John D.</creatorcontrib><creatorcontrib>Murray, Melissa E.</creatorcontrib><creatorcontrib>Dickson, Dennis W.</creatorcontrib><creatorcontrib>Fiesel, Fabienne C.</creatorcontrib><creatorcontrib>Springer, Wolfdieter</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Alzheimer's & dementia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hou, Xu</au><au>Watzlawik, Jens O.</au><au>Cook, Casey</au><au>Liu, Chia‐Chen</au><au>Kang, Silvia S.</au><au>Lin, Wen‐Lang</au><au>DeTure, Michael</au><au>Heckman, Michael G.</au><au>Diehl, Nancy N.</au><au>Al‐Shaikh, Fadi S. Hanna</au><au>Walton, Ronald L.</au><au>Ross, Owen A.</au><au>Melrose, Heather L.</au><au>Ertekin‐Taner, Nilüfer</au><au>Bu, Guojun</au><au>Petrucelli, Leonard</au><au>Fryer, John D.</au><au>Murray, Melissa E.</au><au>Dickson, Dennis W.</au><au>Fiesel, Fabienne C.</au><au>Springer, Wolfdieter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology</atitle><jtitle>Alzheimer's & dementia</jtitle><addtitle>Alzheimers Dement</addtitle><date>2021-03</date><risdate>2021</risdate><volume>17</volume><issue>3</issue><spage>417</spage><epage>430</epage><pages>417-430</pages><issn>1552-5260</issn><eissn>1552-5279</eissn><abstract>Introduction
The cytoprotective PTEN‐induced kinase 1 (PINK1)‐parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis.
Methods
Morphology, levels, and distribution of the mitophagy tag pS65‐Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models.
Results
Analyses revealed significant increases of pS65‐Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho‐tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co‐localization of pS65‐Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed.
Discussion
Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.</abstract><cop>United States</cop><pub>John Wiley and Sons Inc</pub><pmid>33090691</pmid><doi>10.1002/alz.12198</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | Access via Wiley Online Library |
| subjects | Alzheimer's disease autophagy granulovacuolar degeneration lysosomes mitochondria mitophagy Parkin PINK1 PRKN tau ubiquitin |
| title | Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology |
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