Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity
Dyshomeostasis of extracellular zinc and copper has been implicated in β-amyloid aggregation, the major pathology associated with Alzheimer disease. Presenilin mediates the proteolytic cleavage of the β-amyloid precursor protein to release β-amyloid, and mutations in presenilin can cause familial Al...
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| Veröffentlicht in: | The Journal of biological chemistry 2011-03, Vol.286 (11), p.9776-9786 |
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| creator | Greenough, Mark A. Volitakis, Irene Li, Qiao-Xin Laughton, Katrina Evin, Genevieve Ho, Michael Dalziel, Andrew H. Camakaris, James Bush, Ashley I. |
| description | Dyshomeostasis of extracellular zinc and copper has been implicated in β-amyloid aggregation, the major pathology associated with Alzheimer disease. Presenilin mediates the proteolytic cleavage of the β-amyloid precursor protein to release β-amyloid, and mutations in presenilin can cause familial Alzheimer disease. We tested whether presenilin expression affects copper and zinc transport. Studying murine embryonic fibroblasts (MEFs) from presenilin knock-out mice or RNA interference of presenilin expression in HEK293T cells, we observed a marked decrease in saturable uptake of radiolabeled copper and zinc. Measurement of basal metal levels in 6-month-old presenilin 1 heterozygous knock-out (PS1+/−) mice revealed significant deficiencies of copper and zinc in several tissues, including brain. Copper/zinc superoxide dismutase (SOD1) activity was significantly decreased in both presenilin knock-out MEFs and brain tissue of presenilin 1 heterozygous knock-out mice. In the MEFs and PS1+/− brains, copper chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact β-amyloid aggregation through metal ion clearance. |
| doi_str_mv | 10.1074/jbc.M110.163964 |
| format | Article |
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Presenilin mediates the proteolytic cleavage of the β-amyloid precursor protein to release β-amyloid, and mutations in presenilin can cause familial Alzheimer disease. We tested whether presenilin expression affects copper and zinc transport. Studying murine embryonic fibroblasts (MEFs) from presenilin knock-out mice or RNA interference of presenilin expression in HEK293T cells, we observed a marked decrease in saturable uptake of radiolabeled copper and zinc. Measurement of basal metal levels in 6-month-old presenilin 1 heterozygous knock-out (PS1+/−) mice revealed significant deficiencies of copper and zinc in several tissues, including brain. Copper/zinc superoxide dismutase (SOD1) activity was significantly decreased in both presenilin knock-out MEFs and brain tissue of presenilin 1 heterozygous knock-out mice. In the MEFs and PS1+/− brains, copper chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact β-amyloid aggregation through metal ion clearance.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.163964</identifier><identifier>PMID: 21239495</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alzheimer Disease ; Alzheimer Disease - genetics ; Alzheimer Disease - metabolism ; Amyloid - genetics ; Amyloid - metabolism ; Amyloid beta-Protein Precursor - genetics ; Amyloid beta-Protein Precursor - metabolism ; Animals ; Brain - metabolism ; Brain Chemistry - genetics ; CCS ; Copper ; Copper - metabolism ; Embryo, Mammalian - cytology ; Embryo, Mammalian - metabolism ; Fibroblasts - cytology ; Fibroblasts - metabolism ; HEK293 Cells ; Humans ; Mice ; Mice, Knockout ; Molecular Bases of Disease ; Molecular Chaperones - genetics ; Molecular Chaperones - metabolism ; Presenilin ; Presenilin-1 - genetics ; Presenilin-1 - metabolism ; Superoxide Dismutase (SOD) ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Superoxide Dismutase-1 ; Transport Metals ; Zinc ; Zinc - metabolism</subject><ispartof>The Journal of biological chemistry, 2011-03, Vol.286 (11), p.9776-9786</ispartof><rights>2011 © 2011 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2011 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c532t-c783205d89d1c801557c4a177788062f6f53ee654002396e66c23241c9db0cba3</citedby><cites>FETCH-LOGICAL-c532t-c783205d89d1c801557c4a177788062f6f53ee654002396e66c23241c9db0cba3</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/PMC3058959/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058959/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21239495$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Greenough, Mark A.</creatorcontrib><creatorcontrib>Volitakis, Irene</creatorcontrib><creatorcontrib>Li, Qiao-Xin</creatorcontrib><creatorcontrib>Laughton, Katrina</creatorcontrib><creatorcontrib>Evin, Genevieve</creatorcontrib><creatorcontrib>Ho, Michael</creatorcontrib><creatorcontrib>Dalziel, Andrew H.</creatorcontrib><creatorcontrib>Camakaris, James</creatorcontrib><creatorcontrib>Bush, Ashley I.</creatorcontrib><title>Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Dyshomeostasis of extracellular zinc and copper has been implicated in β-amyloid aggregation, the major pathology associated with Alzheimer disease. Presenilin mediates the proteolytic cleavage of the β-amyloid precursor protein to release β-amyloid, and mutations in presenilin can cause familial Alzheimer disease. We tested whether presenilin expression affects copper and zinc transport. Studying murine embryonic fibroblasts (MEFs) from presenilin knock-out mice or RNA interference of presenilin expression in HEK293T cells, we observed a marked decrease in saturable uptake of radiolabeled copper and zinc. Measurement of basal metal levels in 6-month-old presenilin 1 heterozygous knock-out (PS1+/−) mice revealed significant deficiencies of copper and zinc in several tissues, including brain. Copper/zinc superoxide dismutase (SOD1) activity was significantly decreased in both presenilin knock-out MEFs and brain tissue of presenilin 1 heterozygous knock-out mice. In the MEFs and PS1+/− brains, copper chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact β-amyloid aggregation through metal ion clearance.</description><subject>Alzheimer Disease</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - metabolism</subject><subject>Amyloid - genetics</subject><subject>Amyloid - metabolism</subject><subject>Amyloid beta-Protein Precursor - genetics</subject><subject>Amyloid beta-Protein Precursor - metabolism</subject><subject>Animals</subject><subject>Brain - metabolism</subject><subject>Brain Chemistry - genetics</subject><subject>CCS</subject><subject>Copper</subject><subject>Copper - metabolism</subject><subject>Embryo, Mammalian - cytology</subject><subject>Embryo, Mammalian - metabolism</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecular Bases of Disease</subject><subject>Molecular Chaperones - genetics</subject><subject>Molecular Chaperones - metabolism</subject><subject>Presenilin</subject><subject>Presenilin-1 - genetics</subject><subject>Presenilin-1 - metabolism</subject><subject>Superoxide Dismutase (SOD)</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase - metabolism</subject><subject>Superoxide Dismutase-1</subject><subject>Transport Metals</subject><subject>Zinc</subject><subject>Zinc - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU1v1DAQhi0EokvhzA1y45SuP-IkviBVKV9Sq1ZaVkJcLK8z6bpk7WA7K_o_-ME4m20FByxZY2ueeWc0L0KvCT4juCqWdxt9dkWmX8lEWTxBC4JrljNOvj1FC4wpyQXl9Ql6EcIdTqcQ5Dk6oYQyUQi-QL9vPASwpjc2ZDfe7VyELG4ha6Dvx175bD1E9QMy12WNGwbwmbJt9t1YfXhcKWNjug_JZqtScPZQsLq-IHkLA9gWbDwiy0PtapywX6aF7MKE3RhVgOxcR7M38f4letapPsCrYzxF648fvjaf88vrT1-a88tcc0ZjrquaUczbWrRE15hwXulCkaqq6hqXtCs7zgBKXqQ9pO1AWWrKaEG0aDdYbxQ7Re9n3WHc7KDVaUivejl4s1P-Xjpl5L8Za7by1u0lw7wWXCSBd0cB736OEKLcmaDT5pQFNwZZ84rQZMhELmdSexeCh-6xC8FyslImK-VkpZytTBVv_h7ukX_wLgFvZ6BTTqpbb4JcrygmDBPBiWCThJgJSEvcG_AyaANWQ2s86ChbZ_7b_g8si7jA</recordid><startdate>20110318</startdate><enddate>20110318</enddate><creator>Greenough, Mark A.</creator><creator>Volitakis, Irene</creator><creator>Li, Qiao-Xin</creator><creator>Laughton, Katrina</creator><creator>Evin, Genevieve</creator><creator>Ho, Michael</creator><creator>Dalziel, Andrew H.</creator><creator>Camakaris, James</creator><creator>Bush, Ashley I.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110318</creationdate><title>Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity</title><author>Greenough, Mark A. ; Volitakis, Irene ; Li, Qiao-Xin ; Laughton, Katrina ; Evin, Genevieve ; Ho, Michael ; Dalziel, Andrew H. ; Camakaris, James ; Bush, Ashley I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c532t-c783205d89d1c801557c4a177788062f6f53ee654002396e66c23241c9db0cba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Alzheimer Disease</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - metabolism</topic><topic>Amyloid - genetics</topic><topic>Amyloid - metabolism</topic><topic>Amyloid beta-Protein Precursor - genetics</topic><topic>Amyloid beta-Protein Precursor - metabolism</topic><topic>Animals</topic><topic>Brain - metabolism</topic><topic>Brain Chemistry - genetics</topic><topic>CCS</topic><topic>Copper</topic><topic>Copper - metabolism</topic><topic>Embryo, Mammalian - cytology</topic><topic>Embryo, Mammalian - metabolism</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular Bases of Disease</topic><topic>Molecular Chaperones - genetics</topic><topic>Molecular Chaperones - metabolism</topic><topic>Presenilin</topic><topic>Presenilin-1 - genetics</topic><topic>Presenilin-1 - metabolism</topic><topic>Superoxide Dismutase (SOD)</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase - metabolism</topic><topic>Superoxide Dismutase-1</topic><topic>Transport Metals</topic><topic>Zinc</topic><topic>Zinc - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Greenough, Mark A.</creatorcontrib><creatorcontrib>Volitakis, Irene</creatorcontrib><creatorcontrib>Li, Qiao-Xin</creatorcontrib><creatorcontrib>Laughton, Katrina</creatorcontrib><creatorcontrib>Evin, Genevieve</creatorcontrib><creatorcontrib>Ho, Michael</creatorcontrib><creatorcontrib>Dalziel, Andrew H.</creatorcontrib><creatorcontrib>Camakaris, James</creatorcontrib><creatorcontrib>Bush, Ashley I.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><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>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Greenough, Mark A.</au><au>Volitakis, Irene</au><au>Li, Qiao-Xin</au><au>Laughton, Katrina</au><au>Evin, Genevieve</au><au>Ho, Michael</au><au>Dalziel, Andrew H.</au><au>Camakaris, James</au><au>Bush, Ashley I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2011-03-18</date><risdate>2011</risdate><volume>286</volume><issue>11</issue><spage>9776</spage><epage>9786</epage><pages>9776-9786</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Dyshomeostasis of extracellular zinc and copper has been implicated in β-amyloid aggregation, the major pathology associated with Alzheimer disease. Presenilin mediates the proteolytic cleavage of the β-amyloid precursor protein to release β-amyloid, and mutations in presenilin can cause familial Alzheimer disease. We tested whether presenilin expression affects copper and zinc transport. Studying murine embryonic fibroblasts (MEFs) from presenilin knock-out mice or RNA interference of presenilin expression in HEK293T cells, we observed a marked decrease in saturable uptake of radiolabeled copper and zinc. Measurement of basal metal levels in 6-month-old presenilin 1 heterozygous knock-out (PS1+/−) mice revealed significant deficiencies of copper and zinc in several tissues, including brain. Copper/zinc superoxide dismutase (SOD1) activity was significantly decreased in both presenilin knock-out MEFs and brain tissue of presenilin 1 heterozygous knock-out mice. In the MEFs and PS1+/− brains, copper chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact β-amyloid aggregation through metal ion clearance.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21239495</pmid><doi>10.1074/jbc.M110.163964</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alzheimer Disease Alzheimer Disease - genetics Alzheimer Disease - metabolism Amyloid - genetics Amyloid - metabolism Amyloid beta-Protein Precursor - genetics Amyloid beta-Protein Precursor - metabolism Animals Brain - metabolism Brain Chemistry - genetics CCS Copper Copper - metabolism Embryo, Mammalian - cytology Embryo, Mammalian - metabolism Fibroblasts - cytology Fibroblasts - metabolism HEK293 Cells Humans Mice Mice, Knockout Molecular Bases of Disease Molecular Chaperones - genetics Molecular Chaperones - metabolism Presenilin Presenilin-1 - genetics Presenilin-1 - metabolism Superoxide Dismutase (SOD) Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Superoxide Dismutase-1 Transport Metals Zinc Zinc - metabolism |
| title | Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity |
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