Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase
A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein ( PICALM/CALM ) gene, which encodes a protein implicated in the clath...
Gespeichert in:
| Veröffentlicht in: | Nature communications 2014-02, Vol.5 (1), p.3386-3386, Article 3386 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext bestellen |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3386 |
|---|---|
| container_issue | 1 |
| container_start_page | 3386 |
| container_title | Nature communications |
| container_volume | 5 |
| creator | Kanatsu, Kunihiko Morohashi, Yuichi Suzuki, Mai Kuroda, Hiromasa Watanabe, Toshio Tomita, Taisuke Iwatsubo, Takeshi |
| description | A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (
PICALM/CALM
) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu
et al.
show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase. |
| doi_str_mv | 10.1038/ncomms4386 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_C6C</sourceid><recordid>TN_cdi_proquest_miscellaneous_1504153749</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1504153749</sourcerecordid><originalsourceid>FETCH-LOGICAL-c2746-a7b4a09043b201ef161f9bdb0d19f62efac9a0dd1cbb649f768ceeb9e819a2993</originalsourceid><addsrcrecordid>eNptkEtOwzAQhi0EolXphgMgLxEoYDtuEi-r8pSK2MA6cpxJmyqJiyeR6LXgHj0TjloeC6yRPKP59M_MT8gpZ1echcl1Y2xdowyT6IAMBZM84LEID__kAzJGXDH_QsUTKY_JQMhJHAshh2R9A8aBRsjpbDp_ovC-doBY2oY6yDsDSKfbDyloa320uupL6nRb-nrpbLdYUlNpn5ZNUENe6tZLQZNbs2ktlkhtQbefAfZjWj_nhBwVukIY7_8Reb27fZk9BPPn-0e_QmBELKNAx5nUTDEZZoJxKHjEC5XlGcu5KiIBhTZKszznJssiqYo4SgxApiDhSgulwhE53-munX3rANu0LtFAVekGbIcpn3h_JmEse_RihxpnER0U6dqVtXablLO0Nzn9NdnDZ3vdLvP3_qDflnrgcgegbzULcOnKdq7xt_4n9wXfm4qn</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1504153749</pqid></control><display><type>article</type><title>Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase</title><source>Springer Nature OA Free Journals</source><creator>Kanatsu, Kunihiko ; Morohashi, Yuichi ; Suzuki, Mai ; Kuroda, Hiromasa ; Watanabe, Toshio ; Tomita, Taisuke ; Iwatsubo, Takeshi</creator><creatorcontrib>Kanatsu, Kunihiko ; Morohashi, Yuichi ; Suzuki, Mai ; Kuroda, Hiromasa ; Watanabe, Toshio ; Tomita, Taisuke ; Iwatsubo, Takeshi</creatorcontrib><description>A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (
PICALM/CALM
) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu
et al.
show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms4386</identifier><identifier>PMID: 24577224</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/109 ; 14/63 ; 38/89 ; 631/80/313/1461 ; 692/420 ; 692/699/375/365/1283 ; 82/29 ; 82/80 ; Amyloid beta-Peptides - genetics ; Amyloid beta-Peptides - metabolism ; Amyloid Precursor Protein Secretases - genetics ; Amyloid Precursor Protein Secretases - metabolism ; Animals ; Endocytosis - genetics ; Endocytosis - physiology ; Female ; HeLa Cells ; Humanities and Social Sciences ; Humans ; Mice ; Mice, Mutant Strains ; Monomeric Clathrin Assembly Proteins - genetics ; Monomeric Clathrin Assembly Proteins - metabolism ; multidisciplinary ; Science</subject><ispartof>Nature communications, 2014-02, Vol.5 (1), p.3386-3386, Article 3386</ispartof><rights>Springer Nature Limited 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2746-a7b4a09043b201ef161f9bdb0d19f62efac9a0dd1cbb649f768ceeb9e819a2993</citedby><cites>FETCH-LOGICAL-c2746-a7b4a09043b201ef161f9bdb0d19f62efac9a0dd1cbb649f768ceeb9e819a2993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ncomms4386$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://doi.org/10.1038/ncomms4386$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41101,42170,51557</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/ncomms4386$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24577224$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanatsu, Kunihiko</creatorcontrib><creatorcontrib>Morohashi, Yuichi</creatorcontrib><creatorcontrib>Suzuki, Mai</creatorcontrib><creatorcontrib>Kuroda, Hiromasa</creatorcontrib><creatorcontrib>Watanabe, Toshio</creatorcontrib><creatorcontrib>Tomita, Taisuke</creatorcontrib><creatorcontrib>Iwatsubo, Takeshi</creatorcontrib><title>Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (
PICALM/CALM
) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu
et al.
show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.</description><subject>13/1</subject><subject>13/109</subject><subject>14/63</subject><subject>38/89</subject><subject>631/80/313/1461</subject><subject>692/420</subject><subject>692/699/375/365/1283</subject><subject>82/29</subject><subject>82/80</subject><subject>Amyloid beta-Peptides - genetics</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Amyloid Precursor Protein Secretases - genetics</subject><subject>Amyloid Precursor Protein Secretases - metabolism</subject><subject>Animals</subject><subject>Endocytosis - genetics</subject><subject>Endocytosis - physiology</subject><subject>Female</subject><subject>HeLa Cells</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Monomeric Clathrin Assembly Proteins - genetics</subject><subject>Monomeric Clathrin Assembly Proteins - metabolism</subject><subject>multidisciplinary</subject><subject>Science</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtOwzAQhi0EolXphgMgLxEoYDtuEi-r8pSK2MA6cpxJmyqJiyeR6LXgHj0TjloeC6yRPKP59M_MT8gpZ1echcl1Y2xdowyT6IAMBZM84LEID__kAzJGXDH_QsUTKY_JQMhJHAshh2R9A8aBRsjpbDp_ovC-doBY2oY6yDsDSKfbDyloa320uupL6nRb-nrpbLdYUlNpn5ZNUENe6tZLQZNbs2ktlkhtQbefAfZjWj_nhBwVukIY7_8Reb27fZk9BPPn-0e_QmBELKNAx5nUTDEZZoJxKHjEC5XlGcu5KiIBhTZKszznJssiqYo4SgxApiDhSgulwhE53-munX3rANu0LtFAVekGbIcpn3h_JmEse_RihxpnER0U6dqVtXablLO0Nzn9NdnDZ3vdLvP3_qDflnrgcgegbzULcOnKdq7xt_4n9wXfm4qn</recordid><startdate>20140228</startdate><enddate>20140228</enddate><creator>Kanatsu, Kunihiko</creator><creator>Morohashi, Yuichi</creator><creator>Suzuki, Mai</creator><creator>Kuroda, Hiromasa</creator><creator>Watanabe, Toshio</creator><creator>Tomita, Taisuke</creator><creator>Iwatsubo, Takeshi</creator><general>Nature Publishing Group UK</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></search><sort><creationdate>20140228</creationdate><title>Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase</title><author>Kanatsu, Kunihiko ; Morohashi, Yuichi ; Suzuki, Mai ; Kuroda, Hiromasa ; Watanabe, Toshio ; Tomita, Taisuke ; Iwatsubo, Takeshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2746-a7b4a09043b201ef161f9bdb0d19f62efac9a0dd1cbb649f768ceeb9e819a2993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>13/1</topic><topic>13/109</topic><topic>14/63</topic><topic>38/89</topic><topic>631/80/313/1461</topic><topic>692/420</topic><topic>692/699/375/365/1283</topic><topic>82/29</topic><topic>82/80</topic><topic>Amyloid beta-Peptides - genetics</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Amyloid Precursor Protein Secretases - genetics</topic><topic>Amyloid Precursor Protein Secretases - metabolism</topic><topic>Animals</topic><topic>Endocytosis - genetics</topic><topic>Endocytosis - physiology</topic><topic>Female</topic><topic>HeLa Cells</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Monomeric Clathrin Assembly Proteins - genetics</topic><topic>Monomeric Clathrin Assembly Proteins - metabolism</topic><topic>multidisciplinary</topic><topic>Science</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kanatsu, Kunihiko</creatorcontrib><creatorcontrib>Morohashi, Yuichi</creatorcontrib><creatorcontrib>Suzuki, Mai</creatorcontrib><creatorcontrib>Kuroda, Hiromasa</creatorcontrib><creatorcontrib>Watanabe, Toshio</creatorcontrib><creatorcontrib>Tomita, Taisuke</creatorcontrib><creatorcontrib>Iwatsubo, Takeshi</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><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Kanatsu, Kunihiko</au><au>Morohashi, Yuichi</au><au>Suzuki, Mai</au><au>Kuroda, Hiromasa</au><au>Watanabe, Toshio</au><au>Tomita, Taisuke</au><au>Iwatsubo, Takeshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2014-02-28</date><risdate>2014</risdate><volume>5</volume><issue>1</issue><spage>3386</spage><epage>3386</epage><pages>3386-3386</pages><artnum>3386</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (
PICALM/CALM
) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu
et al.
show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24577224</pmid><doi>10.1038/ncomms4386</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext_linktorsrc |
| identifier | ISSN: 2041-1723 |
| ispartof | Nature communications, 2014-02, Vol.5 (1), p.3386-3386, Article 3386 |
| issn | 2041-1723 2041-1723 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1504153749 |
| source | Springer Nature OA Free Journals |
| subjects | 13/1 13/109 14/63 38/89 631/80/313/1461 692/420 692/699/375/365/1283 82/29 82/80 Amyloid beta-Peptides - genetics Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals Endocytosis - genetics Endocytosis - physiology Female HeLa Cells Humanities and Social Sciences Humans Mice Mice, Mutant Strains Monomeric Clathrin Assembly Proteins - genetics Monomeric Clathrin Assembly Proteins - metabolism multidisciplinary Science |
| title | Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-17T20%3A27%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_C6C&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Decreased%20CALM%20expression%20reduces%20A%CE%B242%20to%20total%20A%CE%B2%20ratio%20through%20clathrin-mediated%20endocytosis%20of%20%CE%B3-secretase&rft.jtitle=Nature%20communications&rft.au=Kanatsu,%20Kunihiko&rft.date=2014-02-28&rft.volume=5&rft.issue=1&rft.spage=3386&rft.epage=3386&rft.pages=3386-3386&rft.artnum=3386&rft.issn=2041-1723&rft.eissn=2041-1723&rft_id=info:doi/10.1038/ncomms4386&rft_dat=%3Cproquest_C6C%3E1504153749%3C/proquest_C6C%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1504153749&rft_id=info:pmid/24577224&rfr_iscdi=true |