The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding
Abstract Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN...
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| Veröffentlicht in: | Neurobiology of aging 2013-11, Vol.34 (11), p.2541-2547 |
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| container_title | Neurobiology of aging |
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| creator | De Muynck, Louis Herdewyn, Sarah Beel, Sander Scheveneels, Wendy Van Den Bosch, Ludo Robberecht, Wim Van Damme, Philip |
| description | Abstract Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E–SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect. |
| doi_str_mv | 10.1016/j.neurobiolaging.2013.04.022 |
| format | Article |
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Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E–SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.</description><identifier>ISSN: 0197-4580</identifier><identifier>EISSN: 1558-1497</identifier><identifier>DOI: 10.1016/j.neurobiolaging.2013.04.022</identifier><identifier>PMID: 23706646</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adaptor Proteins, Vesicular Transport - genetics ; Adaptor Proteins, Vesicular Transport - immunology ; Adaptor Proteins, Vesicular Transport - metabolism ; Animals ; Animals, Newborn ; Antibodies - pharmacology ; Binding Sites - drug effects ; Blocking antibody ; Cell Survival - drug effects ; Cells, Cultured ; Cerebral Cortex - cytology ; Cyclic S-Oxides - pharmacology ; Danio rerio ; Embryo, Nonmammalian ; Embryonic Development - drug effects ; Embryonic Development - genetics ; Endocytosis - drug effects ; Enzyme Inhibitors - pharmacology ; Freshwater ; Frontotemporal lobar degeneration ; Granulin E ; Immunoprecipitation ; Intercellular Signaling Peptides and Proteins - metabolism ; Intercellular Signaling Peptides and Proteins - pharmacology ; Internal Medicine ; Morpholines - pharmacology ; Motor Neurons - cytology ; Motor Neurons - drug effects ; Nerve Growth Factors - metabolism ; Nerve Growth Factors - pharmacology ; Neurites - drug effects ; Neurology ; Progranulin ; Protein Structure, Tertiary - physiology ; Rats ; Rats, Wistar ; Sortilin ; Thiazoles - pharmacology ; Zebrafish</subject><ispartof>Neurobiology of aging, 2013-11, Vol.34 (11), p.2541-2547</ispartof><rights>Elsevier Inc.</rights><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-3dffd87034e0ebb83ffd08a159af19ab8ce652c87d8db620bba1afc78bf75d023</citedby><cites>FETCH-LOGICAL-c474t-3dffd87034e0ebb83ffd08a159af19ab8ce652c87d8db620bba1afc78bf75d023</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0197458013001875$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23706646$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De Muynck, Louis</creatorcontrib><creatorcontrib>Herdewyn, Sarah</creatorcontrib><creatorcontrib>Beel, Sander</creatorcontrib><creatorcontrib>Scheveneels, Wendy</creatorcontrib><creatorcontrib>Van Den Bosch, Ludo</creatorcontrib><creatorcontrib>Robberecht, Wim</creatorcontrib><creatorcontrib>Van Damme, Philip</creatorcontrib><title>The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding</title><title>Neurobiology of aging</title><addtitle>Neurobiol Aging</addtitle><description>Abstract Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E–SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.</description><subject>Adaptor Proteins, Vesicular Transport - genetics</subject><subject>Adaptor Proteins, Vesicular Transport - immunology</subject><subject>Adaptor Proteins, Vesicular Transport - metabolism</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Antibodies - pharmacology</subject><subject>Binding Sites - drug effects</subject><subject>Blocking antibody</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Cerebral Cortex - cytology</subject><subject>Cyclic S-Oxides - pharmacology</subject><subject>Danio rerio</subject><subject>Embryo, Nonmammalian</subject><subject>Embryonic Development - drug effects</subject><subject>Embryonic Development - genetics</subject><subject>Endocytosis - drug effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Freshwater</subject><subject>Frontotemporal lobar degeneration</subject><subject>Granulin E</subject><subject>Immunoprecipitation</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Intercellular Signaling Peptides and Proteins - pharmacology</subject><subject>Internal Medicine</subject><subject>Morpholines - pharmacology</subject><subject>Motor Neurons - cytology</subject><subject>Motor Neurons - drug effects</subject><subject>Nerve Growth Factors - metabolism</subject><subject>Nerve Growth Factors - pharmacology</subject><subject>Neurites - drug effects</subject><subject>Neurology</subject><subject>Progranulin</subject><subject>Protein Structure, Tertiary - physiology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Sortilin</subject><subject>Thiazoles - pharmacology</subject><subject>Zebrafish</subject><issn>0197-4580</issn><issn>1558-1497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUk1v1DAQtRCILoW_gHzgwCXpOHFiR0JIqGoBqRIHytnyx2TrJWtv7aRS_z0OWyrBpZzmQ2_ejN4bQt4xqBmw_mxXB1xSND5OeuvDtm6AtTXwGprmGdmwrpMV44N4TjbABlHxTsIJeZXzDgAEF_1LctK0Avqe9xsSrm-Q_iacUzzceEsPJWKaPWYax7XaJh2WyQfq8IDB0RjoXIYe2xfUxb0uiVnmktIQZ5rwdvEJaY6FaQUZH1w59jV5Meop45uHeEp-XF5cn3-prr59_nr-6aqyXPC5at04Oimg5QhojGxLCVKzbtAjG7SRFvuusVI46UzfgDGa6dEKaUbROWjaU_L-yFvuv10wz2rvs8Vp0gHjkhXrAGTRbRiehvIicCdbkAX64Qi1KeaccFSH5Pc63SsGajVH7dTf5qjVHAVcFXPK-NuHTYvZo3sc_uNGAVweAVikufOYVLYeg0VXtLSzctH_76aP_xDZYoK3evqJ95h3cUmhyK-Yyo0C9X19lPVPWAvApOjaX_mqwJk</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>De Muynck, Louis</creator><creator>Herdewyn, Sarah</creator><creator>Beel, Sander</creator><creator>Scheveneels, Wendy</creator><creator>Van Den Bosch, Ludo</creator><creator>Robberecht, Wim</creator><creator>Van Damme, Philip</creator><general>Elsevier Inc</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>7TK</scope><scope>F1W</scope><scope>H95</scope><scope>L.G</scope></search><sort><creationdate>20131101</creationdate><title>The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding</title><author>De Muynck, Louis ; Herdewyn, Sarah ; Beel, Sander ; Scheveneels, Wendy ; Van Den Bosch, Ludo ; Robberecht, Wim ; Van Damme, Philip</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-3dffd87034e0ebb83ffd08a159af19ab8ce652c87d8db620bba1afc78bf75d023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adaptor Proteins, Vesicular Transport - genetics</topic><topic>Adaptor Proteins, Vesicular Transport - immunology</topic><topic>Adaptor Proteins, Vesicular Transport - metabolism</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Antibodies - pharmacology</topic><topic>Binding Sites - drug effects</topic><topic>Blocking antibody</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Cerebral Cortex - cytology</topic><topic>Cyclic S-Oxides - pharmacology</topic><topic>Danio rerio</topic><topic>Embryo, Nonmammalian</topic><topic>Embryonic Development - drug effects</topic><topic>Embryonic Development - genetics</topic><topic>Endocytosis - drug effects</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Freshwater</topic><topic>Frontotemporal lobar degeneration</topic><topic>Granulin E</topic><topic>Immunoprecipitation</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Intercellular Signaling Peptides and Proteins - pharmacology</topic><topic>Internal Medicine</topic><topic>Morpholines - pharmacology</topic><topic>Motor Neurons - cytology</topic><topic>Motor Neurons - drug effects</topic><topic>Nerve Growth Factors - metabolism</topic><topic>Nerve Growth Factors - pharmacology</topic><topic>Neurites - drug effects</topic><topic>Neurology</topic><topic>Progranulin</topic><topic>Protein Structure, Tertiary - physiology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Sortilin</topic><topic>Thiazoles - pharmacology</topic><topic>Zebrafish</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De Muynck, Louis</creatorcontrib><creatorcontrib>Herdewyn, Sarah</creatorcontrib><creatorcontrib>Beel, Sander</creatorcontrib><creatorcontrib>Scheveneels, Wendy</creatorcontrib><creatorcontrib>Van Den Bosch, Ludo</creatorcontrib><creatorcontrib>Robberecht, Wim</creatorcontrib><creatorcontrib>Van Damme, Philip</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>Neurosciences Abstracts</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 1: Biological Sciences & Living Resources</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><jtitle>Neurobiology of aging</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De Muynck, Louis</au><au>Herdewyn, Sarah</au><au>Beel, Sander</au><au>Scheveneels, Wendy</au><au>Van Den Bosch, Ludo</au><au>Robberecht, Wim</au><au>Van Damme, Philip</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding</atitle><jtitle>Neurobiology of aging</jtitle><addtitle>Neurobiol Aging</addtitle><date>2013-11-01</date><risdate>2013</risdate><volume>34</volume><issue>11</issue><spage>2541</spage><epage>2547</epage><pages>2541-2547</pages><issn>0197-4580</issn><eissn>1558-1497</eissn><abstract>Abstract Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E–SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23706646</pmid><doi>10.1016/j.neurobiolaging.2013.04.022</doi><tpages>7</tpages></addata></record> |
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| subjects | Adaptor Proteins, Vesicular Transport - genetics Adaptor Proteins, Vesicular Transport - immunology Adaptor Proteins, Vesicular Transport - metabolism Animals Animals, Newborn Antibodies - pharmacology Binding Sites - drug effects Blocking antibody Cell Survival - drug effects Cells, Cultured Cerebral Cortex - cytology Cyclic S-Oxides - pharmacology Danio rerio Embryo, Nonmammalian Embryonic Development - drug effects Embryonic Development - genetics Endocytosis - drug effects Enzyme Inhibitors - pharmacology Freshwater Frontotemporal lobar degeneration Granulin E Immunoprecipitation Intercellular Signaling Peptides and Proteins - metabolism Intercellular Signaling Peptides and Proteins - pharmacology Internal Medicine Morpholines - pharmacology Motor Neurons - cytology Motor Neurons - drug effects Nerve Growth Factors - metabolism Nerve Growth Factors - pharmacology Neurites - drug effects Neurology Progranulin Protein Structure, Tertiary - physiology Rats Rats, Wistar Sortilin Thiazoles - pharmacology Zebrafish |
| title | The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding |
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