Localization of Phosphorylated ERK/MAP Kinases to Mitochondria and Autophagosomes in Lewy Body Diseases
We previously found that sustained ERK activation contributes to toxicity elicited by the parkinsonian neurotoxin 6‐hydroxydopamine. In addition, substantia nigra neurons from patients with incidental Lewy body disease, Parkinson's disease (PD), and diffuse Lewy body dementia (DLB) display abno...
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| Veröffentlicht in: | Brain pathology (Zurich, Switzerland) Switzerland), 2003-10, Vol.13 (4), p.473-481 |
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| creator | Zhu, Jian-Hui Guo, Fengli Shelburne, John Watkins, Simon Chu, Charleen T. |
| description | We previously found that sustained ERK activation contributes to toxicity elicited by the parkinsonian neurotoxin 6‐hydroxydopamine. In addition, substantia nigra neurons from patients with incidental Lewy body disease, Parkinson's disease (PD), and diffuse Lewy body dementia (DLB) display abnormal phospho‐ERK accumulations in the form of discrete cytoplasmic granules. In this study, we investigated the subcellular localization of phospho‐ERK immunoreactive granules using double label confocal microscopy and immunoelectron microscopy. A small percentage of phospho‐ERK granules colocalized with the early endosome marker Rab5, but not with cathepsin D, 20S proteasome β‐subunit, or cytochrome P450 reductase. Phospho‐ERK immunoreactivity was often associated with mitochondrial proteins (MnSOD, 60 kDa and 110 kDa mitochondrial antigens), and some vesicular‐appearing phospho‐ERK granules appeared to envelop enlarged mitochondria by confocal laser scanning microscopy. Ultrastructural immuno‐gold studies revealed phospho‐ERK labeling in mitochondria and in association with bundles of ∼10 nm fibrils. Heavily labeled mitochondria were observed within autophagosomes. As mitochondrial pathology may play a pivotal role in Parkinson's and other related neurodegenerative diseases, these studies suggest a potential interaction between dysfunctional mitochondria, autophagy, and ERK signaling pathways. |
| doi_str_mv | 10.1111/j.1750-3639.2003.tb00478.x |
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In addition, substantia nigra neurons from patients with incidental Lewy body disease, Parkinson's disease (PD), and diffuse Lewy body dementia (DLB) display abnormal phospho‐ERK accumulations in the form of discrete cytoplasmic granules. In this study, we investigated the subcellular localization of phospho‐ERK immunoreactive granules using double label confocal microscopy and immunoelectron microscopy. A small percentage of phospho‐ERK granules colocalized with the early endosome marker Rab5, but not with cathepsin D, 20S proteasome β‐subunit, or cytochrome P450 reductase. Phospho‐ERK immunoreactivity was often associated with mitochondrial proteins (MnSOD, 60 kDa and 110 kDa mitochondrial antigens), and some vesicular‐appearing phospho‐ERK granules appeared to envelop enlarged mitochondria by confocal laser scanning microscopy. Ultrastructural immuno‐gold studies revealed phospho‐ERK labeling in mitochondria and in association with bundles of ∼10 nm fibrils. Heavily labeled mitochondria were observed within autophagosomes. As mitochondrial pathology may play a pivotal role in Parkinson's and other related neurodegenerative diseases, these studies suggest a potential interaction between dysfunctional mitochondria, autophagy, and ERK signaling pathways.</description><identifier>ISSN: 1015-6305</identifier><identifier>EISSN: 1750-3639</identifier><identifier>DOI: 10.1111/j.1750-3639.2003.tb00478.x</identifier><identifier>PMID: 14655753</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Aged ; Aged, 80 and over ; Autophagy ; Cathepsin D - metabolism ; Cytochrome P-450 Enzyme System - metabolism ; Endosomes - metabolism ; Endosomes - pathology ; Endosomes - ultrastructure ; Female ; Fluorescent Antibody Technique - methods ; Humans ; Lewy Body Disease - enzymology ; Lewy Body Disease - metabolism ; Lewy Body Disease - pathology ; Lysosomes - metabolism ; Lysosomes - pathology ; Lysosomes - ultrastructure ; Male ; Mesencephalon - metabolism ; Mesencephalon - pathology ; Mesencephalon - ultrastructure ; Microscopy, Confocal - methods ; Microscopy, Immunoelectron - methods ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondria - ultrastructure ; Mitogen-Activated Protein Kinases - metabolism ; Parkinson Disease - enzymology ; Parkinson Disease - metabolism ; Parkinson Disease - pathology ; Protein-Serine-Threonine Kinases - metabolism ; rab5 GTP-Binding Proteins - metabolism ; Superoxide Dismutase - metabolism</subject><ispartof>Brain pathology (Zurich, Switzerland), 2003-10, Vol.13 (4), p.473-481</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c5243-dab0ad6e54d884c1b2180a5e63ddb47beb2647ccb02d969db888c929a39114aa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1911206/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1911206/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,1418,27929,27930,45579,45580,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14655753$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, Jian-Hui</creatorcontrib><creatorcontrib>Guo, Fengli</creatorcontrib><creatorcontrib>Shelburne, John</creatorcontrib><creatorcontrib>Watkins, Simon</creatorcontrib><creatorcontrib>Chu, Charleen T.</creatorcontrib><title>Localization of Phosphorylated ERK/MAP Kinases to Mitochondria and Autophagosomes in Lewy Body Diseases</title><title>Brain pathology (Zurich, Switzerland)</title><addtitle>Brain Pathol</addtitle><description>We previously found that sustained ERK activation contributes to toxicity elicited by the parkinsonian neurotoxin 6‐hydroxydopamine. In addition, substantia nigra neurons from patients with incidental Lewy body disease, Parkinson's disease (PD), and diffuse Lewy body dementia (DLB) display abnormal phospho‐ERK accumulations in the form of discrete cytoplasmic granules. In this study, we investigated the subcellular localization of phospho‐ERK immunoreactive granules using double label confocal microscopy and immunoelectron microscopy. A small percentage of phospho‐ERK granules colocalized with the early endosome marker Rab5, but not with cathepsin D, 20S proteasome β‐subunit, or cytochrome P450 reductase. Phospho‐ERK immunoreactivity was often associated with mitochondrial proteins (MnSOD, 60 kDa and 110 kDa mitochondrial antigens), and some vesicular‐appearing phospho‐ERK granules appeared to envelop enlarged mitochondria by confocal laser scanning microscopy. Ultrastructural immuno‐gold studies revealed phospho‐ERK labeling in mitochondria and in association with bundles of ∼10 nm fibrils. Heavily labeled mitochondria were observed within autophagosomes. As mitochondrial pathology may play a pivotal role in Parkinson's and other related neurodegenerative diseases, these studies suggest a potential interaction between dysfunctional mitochondria, autophagy, and ERK signaling pathways.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Autophagy</subject><subject>Cathepsin D - metabolism</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Endosomes - metabolism</subject><subject>Endosomes - pathology</subject><subject>Endosomes - ultrastructure</subject><subject>Female</subject><subject>Fluorescent Antibody Technique - methods</subject><subject>Humans</subject><subject>Lewy Body Disease - enzymology</subject><subject>Lewy Body Disease - metabolism</subject><subject>Lewy Body Disease - pathology</subject><subject>Lysosomes - metabolism</subject><subject>Lysosomes - pathology</subject><subject>Lysosomes - ultrastructure</subject><subject>Male</subject><subject>Mesencephalon - metabolism</subject><subject>Mesencephalon - pathology</subject><subject>Mesencephalon - ultrastructure</subject><subject>Microscopy, Confocal - methods</subject><subject>Microscopy, Immunoelectron - methods</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondria - ultrastructure</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Parkinson Disease - enzymology</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson Disease - pathology</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>rab5 GTP-Binding Proteins - metabolism</subject><subject>Superoxide Dismutase - metabolism</subject><issn>1015-6305</issn><issn>1750-3639</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkF1v0zAUhi0EYmPwF5DFfTI7_kjCBVJXtoHWQZmGxp11_NHGJY2rOGPNfv0StergEt_Y0vH7nHMehD5QktLhnK5SmguSMMnKNCOEpZ0mhOdFun2Bjg-ll8ObUJFIRsQRehPjihBaylK8RkeUSyFywY7RchYM1P4ROh8aHBZ4XoW4qULb19A5i89vrk6vJ3N85RuILuIu4GvfBVOFxrYeMDQWT-67sKlgGWJYD198g2fuocdnwfb4s49uDL5FrxZQR_duf5-gnxfnt9Mvyez75dfpZJYYkXGWWNAErHSC26LghuqMFgSEk8xazXPtdCZ5bowmmR12sbooClNmJbCSUg7ATtCnHXdzr9fOGtd0LdRq0_o1tL0K4NW_lcZXahn-KDoAMiIHwMcdwLQhxtYtDllK1KhfrdToWI2O1ahf7fWr7RB-_3f35-je9_N4D752_X-g1dl8wvMRkOwAPnZuewBA-1vJnOVC3X27VNNf07vi4vaHumFPvJCnPA</recordid><startdate>200310</startdate><enddate>200310</enddate><creator>Zhu, Jian-Hui</creator><creator>Guo, Fengli</creator><creator>Shelburne, John</creator><creator>Watkins, Simon</creator><creator>Chu, Charleen T.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><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>5PM</scope></search><sort><creationdate>200310</creationdate><title>Localization of Phosphorylated ERK/MAP Kinases to Mitochondria and Autophagosomes in Lewy Body Diseases</title><author>Zhu, Jian-Hui ; Guo, Fengli ; Shelburne, John ; Watkins, Simon ; Chu, Charleen T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5243-dab0ad6e54d884c1b2180a5e63ddb47beb2647ccb02d969db888c929a39114aa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Autophagy</topic><topic>Cathepsin D - metabolism</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Endosomes - metabolism</topic><topic>Endosomes - pathology</topic><topic>Endosomes - ultrastructure</topic><topic>Female</topic><topic>Fluorescent Antibody Technique - methods</topic><topic>Humans</topic><topic>Lewy Body Disease - enzymology</topic><topic>Lewy Body Disease - metabolism</topic><topic>Lewy Body Disease - pathology</topic><topic>Lysosomes - metabolism</topic><topic>Lysosomes - pathology</topic><topic>Lysosomes - ultrastructure</topic><topic>Male</topic><topic>Mesencephalon - metabolism</topic><topic>Mesencephalon - pathology</topic><topic>Mesencephalon - ultrastructure</topic><topic>Microscopy, Confocal - methods</topic><topic>Microscopy, Immunoelectron - methods</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - pathology</topic><topic>Mitochondria - ultrastructure</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Parkinson Disease - enzymology</topic><topic>Parkinson Disease - metabolism</topic><topic>Parkinson Disease - pathology</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>rab5 GTP-Binding Proteins - metabolism</topic><topic>Superoxide Dismutase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, Jian-Hui</creatorcontrib><creatorcontrib>Guo, Fengli</creatorcontrib><creatorcontrib>Shelburne, John</creatorcontrib><creatorcontrib>Watkins, Simon</creatorcontrib><creatorcontrib>Chu, Charleen T.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Brain pathology (Zurich, Switzerland)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Jian-Hui</au><au>Guo, Fengli</au><au>Shelburne, John</au><au>Watkins, Simon</au><au>Chu, Charleen T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Localization of Phosphorylated ERK/MAP Kinases to Mitochondria and Autophagosomes in Lewy Body Diseases</atitle><jtitle>Brain pathology (Zurich, Switzerland)</jtitle><addtitle>Brain Pathol</addtitle><date>2003-10</date><risdate>2003</risdate><volume>13</volume><issue>4</issue><spage>473</spage><epage>481</epage><pages>473-481</pages><issn>1015-6305</issn><eissn>1750-3639</eissn><abstract>We previously found that sustained ERK activation contributes to toxicity elicited by the parkinsonian neurotoxin 6‐hydroxydopamine. In addition, substantia nigra neurons from patients with incidental Lewy body disease, Parkinson's disease (PD), and diffuse Lewy body dementia (DLB) display abnormal phospho‐ERK accumulations in the form of discrete cytoplasmic granules. In this study, we investigated the subcellular localization of phospho‐ERK immunoreactive granules using double label confocal microscopy and immunoelectron microscopy. A small percentage of phospho‐ERK granules colocalized with the early endosome marker Rab5, but not with cathepsin D, 20S proteasome β‐subunit, or cytochrome P450 reductase. Phospho‐ERK immunoreactivity was often associated with mitochondrial proteins (MnSOD, 60 kDa and 110 kDa mitochondrial antigens), and some vesicular‐appearing phospho‐ERK granules appeared to envelop enlarged mitochondria by confocal laser scanning microscopy. Ultrastructural immuno‐gold studies revealed phospho‐ERK labeling in mitochondria and in association with bundles of ∼10 nm fibrils. Heavily labeled mitochondria were observed within autophagosomes. As mitochondrial pathology may play a pivotal role in Parkinson's and other related neurodegenerative diseases, these studies suggest a potential interaction between dysfunctional mitochondria, autophagy, and ERK signaling pathways.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>14655753</pmid><doi>10.1111/j.1750-3639.2003.tb00478.x</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Aged, 80 and over Autophagy Cathepsin D - metabolism Cytochrome P-450 Enzyme System - metabolism Endosomes - metabolism Endosomes - pathology Endosomes - ultrastructure Female Fluorescent Antibody Technique - methods Humans Lewy Body Disease - enzymology Lewy Body Disease - metabolism Lewy Body Disease - pathology Lysosomes - metabolism Lysosomes - pathology Lysosomes - ultrastructure Male Mesencephalon - metabolism Mesencephalon - pathology Mesencephalon - ultrastructure Microscopy, Confocal - methods Microscopy, Immunoelectron - methods Mitochondria - metabolism Mitochondria - pathology Mitochondria - ultrastructure Mitogen-Activated Protein Kinases - metabolism Parkinson Disease - enzymology Parkinson Disease - metabolism Parkinson Disease - pathology Protein-Serine-Threonine Kinases - metabolism rab5 GTP-Binding Proteins - metabolism Superoxide Dismutase - metabolism |
| title | Localization of Phosphorylated ERK/MAP Kinases to Mitochondria and Autophagosomes in Lewy Body Diseases |
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