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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins</title>
<author><name sortKey="Page, Lesley J" sort="Page, Lesley J" uniqKey="Page L" first="Lesley J." last="Page">Lesley J. Page</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Suk, Ji Young" sort="Suk, Ji Young" uniqKey="Suk J" first="Ji Young" last="Suk">Ji Young Suk</name>
<affiliation><nlm:aff id="aff2">Departments of Chemistry and Molecular and Experimental Medicine,</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bazhenova, Lyudmila" sort="Bazhenova, Lyudmila" uniqKey="Bazhenova L" first="Lyudmila" last="Bazhenova">Lyudmila Bazhenova</name>
<affiliation><nlm:aff id="aff2">Departments of Chemistry and Molecular and Experimental Medicine,</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fleming, Sheila M" sort="Fleming, Sheila M" uniqKey="Fleming S" first="Sheila M." last="Fleming">Sheila M. Fleming</name>
<affiliation><nlm:aff id="aff6">Department of Neurobiology, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wood, Malcolm" sort="Wood, Malcolm" uniqKey="Wood M" first="Malcolm" last="Wood">Malcolm Wood</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jiang, Yun" sort="Jiang, Yun" uniqKey="Jiang Y" first="Yun" last="Jiang">Yun Jiang</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Guo, Ling T" sort="Guo, Ling T" uniqKey="Guo L" first="Ling T." last="Guo">Ling T. Guo</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mizisin, Andrew P" sort="Mizisin, Andrew P" uniqKey="Mizisin A" first="Andrew P." last="Mizisin">Andrew P. Mizisin</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kisilevsky, Robert" sort="Kisilevsky, Robert" uniqKey="Kisilevsky R" first="Robert" last="Kisilevsky">Robert Kisilevsky</name>
<affiliation><nlm:aff id="aff8">Departments of Pathology and Molecular Medicine, and Biochemistry, Queen's University, Kingston, ON, Canada K7L 3N6</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shelton, G Diane" sort="Shelton, G Diane" uniqKey="Shelton G" first="G. Diane" last="Shelton">G. Diane Shelton</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Balch, William E" sort="Balch, William E" uniqKey="Balch W" first="William E." last="Balch">William E. Balch</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="aff3">Department of Chemical Physiology</nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="aff4">Institute for Childhood and Neglected Diseases</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kelly, Jeffery W" sort="Kelly, Jeffery W" uniqKey="Kelly J" first="Jeffery W." last="Kelly">Jeffery W. Kelly</name>
<affiliation><nlm:aff id="aff2">Departments of Chemistry and Molecular and Experimental Medicine,</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">19549824</idno>
<idno type="pmc">2708763</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708763</idno>
<idno type="RBID">PMC:2708763</idno>
<idno type="doi">10.1073/pnas.0811753106</idno>
<date when="2009">2009</date>
<idno type="wicri:Area/Pmc/Corpus">000654</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000654</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins</title>
<author><name sortKey="Page, Lesley J" sort="Page, Lesley J" uniqKey="Page L" first="Lesley J." last="Page">Lesley J. Page</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Suk, Ji Young" sort="Suk, Ji Young" uniqKey="Suk J" first="Ji Young" last="Suk">Ji Young Suk</name>
<affiliation><nlm:aff id="aff2">Departments of Chemistry and Molecular and Experimental Medicine,</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bazhenova, Lyudmila" sort="Bazhenova, Lyudmila" uniqKey="Bazhenova L" first="Lyudmila" last="Bazhenova">Lyudmila Bazhenova</name>
<affiliation><nlm:aff id="aff2">Departments of Chemistry and Molecular and Experimental Medicine,</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fleming, Sheila M" sort="Fleming, Sheila M" uniqKey="Fleming S" first="Sheila M." last="Fleming">Sheila M. Fleming</name>
<affiliation><nlm:aff id="aff6">Department of Neurobiology, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wood, Malcolm" sort="Wood, Malcolm" uniqKey="Wood M" first="Malcolm" last="Wood">Malcolm Wood</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jiang, Yun" sort="Jiang, Yun" uniqKey="Jiang Y" first="Yun" last="Jiang">Yun Jiang</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Guo, Ling T" sort="Guo, Ling T" uniqKey="Guo L" first="Ling T." last="Guo">Ling T. Guo</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mizisin, Andrew P" sort="Mizisin, Andrew P" uniqKey="Mizisin A" first="Andrew P." last="Mizisin">Andrew P. Mizisin</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kisilevsky, Robert" sort="Kisilevsky, Robert" uniqKey="Kisilevsky R" first="Robert" last="Kisilevsky">Robert Kisilevsky</name>
<affiliation><nlm:aff id="aff8">Departments of Pathology and Molecular Medicine, and Biochemistry, Queen's University, Kingston, ON, Canada K7L 3N6</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shelton, G Diane" sort="Shelton, G Diane" uniqKey="Shelton G" first="G. Diane" last="Shelton">G. Diane Shelton</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Department of Pathology, University of California at San Diego, La Jolla, CA 92093</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Balch, William E" sort="Balch, William E" uniqKey="Balch W" first="William E." last="Balch">William E. Balch</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="aff3">Department of Chemical Physiology</nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="aff4">Institute for Childhood and Neglected Diseases</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kelly, Jeffery W" sort="Kelly, Jeffery W" uniqKey="Kelly J" first="Jeffery W." last="Kelly">Jeffery W. Kelly</name>
<affiliation><nlm:aff id="aff2">Departments of Chemistry and Molecular and Experimental Medicine,</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff5">The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title>
<idno type="ISSN">0027-8424</idno>
<idno type="eISSN">1091-6490</idno>
<imprint><date when="2009">2009</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Familial amyloidosis of Finnish type (FAF) is a systemic amyloid disease associated with the deposition of proteolytic fragments of mutant (D187N/Y) plasma gelsolin. We report a mouse model of FAF featuring a muscle-specific promoter to drive D187N gelsolin synthesis. This model recapitulates the aberrant endoproteolytic cascade and the aging-associated extracellular amyloid deposition of FAF. Amyloidogenesis is observed only in tissues synthesizing human D187N gelsolin, despite the presence of full-length D187N gelsolin and its 68-kDa cleavage product in blood—demonstrating the importance of local synthesis in FAF. Loss of muscle strength was progressive in homozygous D187N gelsolin mice. The presence of misfolding-prone D187N gelsolin appears to exacerbate the age-associated decline in cellular protein homeostasis (proteostasis), reflected by the intracellular deposition of numerous proteins, a characteristic of the most common degenerative muscle disease of aging humans, sporadic inclusion body myositis.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id>
<journal-id journal-id-type="hwp">pnas</journal-id>
<journal-id journal-id-type="pmc">pnas</journal-id>
<journal-id journal-id-type="publisher-id">PNAS</journal-id>
<journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title>
</journal-title-group>
<issn pub-type="ppub">0027-8424</issn>
<issn pub-type="epub">1091-6490</issn>
<publisher><publisher-name>National Academy of Sciences</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">19549824</article-id>
<article-id pub-id-type="pmc">2708763</article-id>
<article-id pub-id-type="publisher-id">8374</article-id>
<article-id pub-id-type="doi">10.1073/pnas.0811753106</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject>
<subj-group><subject>Cell Biology</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Page</surname>
<given-names>Lesley J.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Suk</surname>
<given-names>Ji Young</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="author-notes" rid="FN1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bazhenova</surname>
<given-names>Lyudmila</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="author-notes" rid="FN1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fleming</surname>
<given-names>Sheila M.</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wood</surname>
<given-names>Malcolm</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jiang</surname>
<given-names>Yun</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guo</surname>
<given-names>Ling T.</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mizisin</surname>
<given-names>Andrew P.</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kisilevsky</surname>
<given-names>Robert</given-names>
</name>
<xref ref-type="aff" rid="aff8"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shelton</surname>
<given-names>G. Diane</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Balch</surname>
<given-names>William E.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>f</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>g</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>h</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kelly</surname>
<given-names>Jeffery W.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>h</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>2</sup>
</xref>
</contrib>
<aff id="aff1">Department of<sup>a</sup>
Cell Biology,</aff>
<aff id="aff2"><sup>b</sup>
Departments of Chemistry and Molecular and Experimental Medicine,</aff>
<aff id="aff3"><sup>f</sup>
Department of Chemical Physiology, and</aff>
<aff id="aff4"><sup>g</sup>
Institute for Childhood and Neglected Diseases, and</aff>
<aff id="aff5"><sup>h</sup>
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;</aff>
<aff id="aff6"><sup>c</sup>
Department of Neurobiology, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095;</aff>
<aff id="aff7"><sup>d</sup>
Department of Pathology, University of California at San Diego, La Jolla, CA 92093; and</aff>
<aff id="aff8"><sup>e</sup>
Departments of Pathology and Molecular Medicine, and Biochemistry, Queen's University, Kingston, ON, Canada K7L 3N6</aff>
</contrib-group>
<author-notes><corresp id="cor1"><sup>2</sup>
To whom correspondence may be addressed. E-mail: <email>webalch@scripps.edu</email>
or <email>jkelly@scripps.edu</email>
</corresp>
<fn fn-type="edited-by"><p>Edited by Charles Weissmann, Scripps Florida, Jupiter, FL, and approved May 1, 2009</p>
</fn>
<fn fn-type="con"><p>Author contributions: L.J.P., W.E.B., and J.W.K. designed research; L.J.P., J.Y.S., L.B., Y.J., L.T.G., and A.P.M. performed research; L.J.P., S.M.F., M.W., Y.J., L.T.G., A.P.M., R.K., G.D.S., and W.E.B. analyzed data; L.J.P., G.D.S., W.E.B., and J.W.K. wrote the paper.</p>
</fn>
<fn id="FN1" fn-type="equal"><p><sup>1</sup>
J.Y.S. and L.B. contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>7</day>
<month>7</month>
<year>2009</year>
</pub-date>
<pub-date pub-type="epub"><day>19</day>
<month>6</month>
<year>2009</year>
</pub-date>
<volume>106</volume>
<issue>27</issue>
<fpage>11125</fpage>
<lpage>11130</lpage>
<history><date date-type="received"><day>20</day>
<month>11</month>
<year>2008</year>
</date>
</history>
<permissions></permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zpq02709011125.pdf"></self-uri>
<abstract><p>Familial amyloidosis of Finnish type (FAF) is a systemic amyloid disease associated with the deposition of proteolytic fragments of mutant (D187N/Y) plasma gelsolin. We report a mouse model of FAF featuring a muscle-specific promoter to drive D187N gelsolin synthesis. This model recapitulates the aberrant endoproteolytic cascade and the aging-associated extracellular amyloid deposition of FAF. Amyloidogenesis is observed only in tissues synthesizing human D187N gelsolin, despite the presence of full-length D187N gelsolin and its 68-kDa cleavage product in blood—demonstrating the importance of local synthesis in FAF. Loss of muscle strength was progressive in homozygous D187N gelsolin mice. The presence of misfolding-prone D187N gelsolin appears to exacerbate the age-associated decline in cellular protein homeostasis (proteostasis), reflected by the intracellular deposition of numerous proteins, a characteristic of the most common degenerative muscle disease of aging humans, sporadic inclusion body myositis.</p>
</abstract>
<kwd-group><kwd>amyloid</kwd>
<kwd>proteostasis</kwd>
<kwd>sporadic inclusion body myositis</kwd>
<kwd>FAF mouse</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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