Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms
Identifieur interne : 000463 ( Pmc/Checkpoint ); précédent : 000462; suivant : 000464Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms
Auteurs : Leslie I. Grad [Canada] ; Justin J. Yerbury [Australie] ; Bradley J. Turner ; William C. Guest [Canada] ; Edward Pokrishevsky [Canada] ; Megan A. O Eill [Canada] ; Anat Yanai [Canada] ; Judith M. Silverman [Canada] ; Rafaa Zeineddine [Australie] ; Lisa Corcoran [Australie] ; Janet R. Kumita [Royaume-Uni] ; Leila M. Luheshi [Royaume-Uni] ; Masoud Yousefi [Canada] ; Bradley M. Coleman [Australie] ; Andrew F. Hill [Australie] ; Steven S. Plotkin [Canada] ; Ian R. Mackenzie [Canada] ; Neil R. Cashman [Canada]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2014.
Abstract
Amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease, is associated with mutation and misfolding of the Cu/Zn superoxide dismutase (SOD1) protein. Prior studies found that mutant misfolded SOD1 can convert wild-type (WT) SOD1 to a misfolded form inside living cells in a prion-like fashion. We now report that misfolded WT SOD1 can be transmitted from cell to cell, and that propagated protein misfolding can be perpetuated. Misfolded SOD1 transmission between cells can be mediated through release and uptake of protein aggregates or via small membrane-bounded transport vesicles called exosomes. These mechanisms may help explain why sporadic ALS, without a known genetic cause, can spread systematically from region to region in a progressive manner.
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DOI: 10.1073/pnas.1312245111
PubMed: 24550511
PubMed Central: 3948312
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Yerbury</name><affiliation wicri:level="1"><nlm:aff id="aff3">Illawarra Health and Medical Research Institute,<institution>University of Wollongong</institution>, Wollongong, NSW 2522,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Turner, Bradley J" sort="Turner, Bradley J" uniqKey="Turner B" first="Bradley J." last="Turner">Bradley J. Turner</name><affiliation><nlm:aff wicri:cut=" and" id="aff4">Florey Institute of Neuroscience and Mental Health</nlm:aff></affiliation></author><author><name sortKey="Guest, William C" sort="Guest, William C" uniqKey="Guest W" first="William C." last="Guest">William C. Guest</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pokrishevsky, Edward" sort="Pokrishevsky, Edward" uniqKey="Pokrishevsky E" first="Edward" last="Pokrishevsky">Edward Pokrishevsky</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="O Eill, Megan A" sort="O Eill, Megan A" uniqKey="O Eill M" first="Megan A." last="O Eill">Megan A. O Eill</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yanai, Anat" sort="Yanai, Anat" uniqKey="Yanai A" first="Anat" last="Yanai">Anat Yanai</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Silverman, Judith M" sort="Silverman, Judith M" uniqKey="Silverman J" first="Judith M." last="Silverman">Judith M. Silverman</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zeineddine, Rafaa" sort="Zeineddine, Rafaa" uniqKey="Zeineddine R" first="Rafaa" last="Zeineddine">Rafaa Zeineddine</name><affiliation wicri:level="1"><nlm:aff id="aff3">Illawarra Health and Medical Research Institute,<institution>University of Wollongong</institution>, Wollongong, NSW 2522,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Corcoran, Lisa" sort="Corcoran, Lisa" uniqKey="Corcoran L" first="Lisa" last="Corcoran">Lisa Corcoran</name><affiliation wicri:level="1"><nlm:aff id="aff3">Illawarra Health and Medical Research Institute,<institution>University of Wollongong</institution>, Wollongong, NSW 2522,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kumita, Janet R" sort="Kumita, Janet R" uniqKey="Kumita J" first="Janet R." last="Kumita">Janet R. Kumita</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Chemistry,<institution>University of Cambridge</institution>, Cambridge CB2 1EW,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Luheshi, Leila M" sort="Luheshi, Leila M" uniqKey="Luheshi L" first="Leila M." last="Luheshi">Leila M. Luheshi</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Chemistry,<institution>University of Cambridge</institution>, Cambridge CB2 1EW,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yousefi, Masoud" sort="Yousefi, Masoud" uniqKey="Yousefi M" first="Masoud" last="Yousefi">Masoud Yousefi</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Coleman, Bradley M" sort="Coleman, Bradley M" uniqKey="Coleman B" first="Bradley M." last="Coleman">Bradley M. Coleman</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute,<institution>University of Melbourne</institution>, Parkville, VIC 3010,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hill, Andrew F" sort="Hill, Andrew F" uniqKey="Hill A" first="Andrew F." last="Hill">Andrew F. Hill</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute,<institution>University of Melbourne</institution>, Parkville, VIC 3010,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Plotkin, Steven S" sort="Plotkin, Steven S" uniqKey="Plotkin S" first="Steven S." last="Plotkin">Steven S. Plotkin</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff2">Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada V6T 1Z1</nlm:aff><country>Canada</country><wicri:regionArea>Department of Physics and Astronomy, University of British Columbia, Vancouver, BC</wicri:regionArea><wicri:noRegion>BC</wicri:noRegion></affiliation></author><author><name sortKey="Mackenzie, Ian R" sort="Mackenzie, Ian R" uniqKey="Mackenzie I" first="Ian R." last="Mackenzie">Ian R. Mackenzie</name><affiliation wicri:level="1"><nlm:aff id="aff7">Department of Pathology and Laboratory Medicine,<institution>University of British Columbia</institution>, Vancouver, BC,<country>Canada</country> V5Z 1M9</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cashman, Neil R" sort="Cashman, Neil R" uniqKey="Cashman N" first="Neil R." last="Cashman">Neil R. Cashman</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24550511</idno><idno type="pmc">3948312</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948312</idno><idno type="RBID">PMC:3948312</idno><idno type="doi">10.1073/pnas.1312245111</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000669</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000669</idno><idno type="wicri:Area/Pmc/Curation">000669</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000669</idno><idno type="wicri:Area/Pmc/Checkpoint">000463</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000463</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms</title><author><name sortKey="Grad, Leslie I" sort="Grad, Leslie I" uniqKey="Grad L" first="Leslie I." last="Grad">Leslie I. Grad</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yerbury, Justin J" sort="Yerbury, Justin J" uniqKey="Yerbury J" first="Justin J." last="Yerbury">Justin J. Yerbury</name><affiliation wicri:level="1"><nlm:aff id="aff3">Illawarra Health and Medical Research Institute,<institution>University of Wollongong</institution>, Wollongong, NSW 2522,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Turner, Bradley J" sort="Turner, Bradley J" uniqKey="Turner B" first="Bradley J." last="Turner">Bradley J. Turner</name><affiliation><nlm:aff wicri:cut=" and" id="aff4">Florey Institute of Neuroscience and Mental Health</nlm:aff></affiliation></author><author><name sortKey="Guest, William C" sort="Guest, William C" uniqKey="Guest W" first="William C." last="Guest">William C. Guest</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pokrishevsky, Edward" sort="Pokrishevsky, Edward" uniqKey="Pokrishevsky E" first="Edward" last="Pokrishevsky">Edward Pokrishevsky</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="O Eill, Megan A" sort="O Eill, Megan A" uniqKey="O Eill M" first="Megan A." last="O Eill">Megan A. O Eill</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yanai, Anat" sort="Yanai, Anat" uniqKey="Yanai A" first="Anat" last="Yanai">Anat Yanai</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Silverman, Judith M" sort="Silverman, Judith M" uniqKey="Silverman J" first="Judith M." last="Silverman">Judith M. Silverman</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zeineddine, Rafaa" sort="Zeineddine, Rafaa" uniqKey="Zeineddine R" first="Rafaa" last="Zeineddine">Rafaa Zeineddine</name><affiliation wicri:level="1"><nlm:aff id="aff3">Illawarra Health and Medical Research Institute,<institution>University of Wollongong</institution>, Wollongong, NSW 2522,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Corcoran, Lisa" sort="Corcoran, Lisa" uniqKey="Corcoran L" first="Lisa" last="Corcoran">Lisa Corcoran</name><affiliation wicri:level="1"><nlm:aff id="aff3">Illawarra Health and Medical Research Institute,<institution>University of Wollongong</institution>, Wollongong, NSW 2522,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kumita, Janet R" sort="Kumita, Janet R" uniqKey="Kumita J" first="Janet R." last="Kumita">Janet R. Kumita</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Chemistry,<institution>University of Cambridge</institution>, Cambridge CB2 1EW,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Luheshi, Leila M" sort="Luheshi, Leila M" uniqKey="Luheshi L" first="Leila M." last="Luheshi">Leila M. Luheshi</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Chemistry,<institution>University of Cambridge</institution>, Cambridge CB2 1EW,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yousefi, Masoud" sort="Yousefi, Masoud" uniqKey="Yousefi M" first="Masoud" last="Yousefi">Masoud Yousefi</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Coleman, Bradley M" sort="Coleman, Bradley M" uniqKey="Coleman B" first="Bradley M." last="Coleman">Bradley M. Coleman</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute,<institution>University of Melbourne</institution>, Parkville, VIC 3010,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hill, Andrew F" sort="Hill, Andrew F" uniqKey="Hill A" first="Andrew F." last="Hill">Andrew F. Hill</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute,<institution>University of Melbourne</institution>, Parkville, VIC 3010,<country>Australia</country>;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Plotkin, Steven S" sort="Plotkin, Steven S" uniqKey="Plotkin S" first="Steven S." last="Plotkin">Steven S. Plotkin</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff2">Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada V6T 1Z1</nlm:aff><country>Canada</country><wicri:regionArea>Department of Physics and Astronomy, University of British Columbia, Vancouver, BC</wicri:regionArea><wicri:noRegion>BC</wicri:noRegion></affiliation></author><author><name sortKey="Mackenzie, Ian R" sort="Mackenzie, Ian R" uniqKey="Mackenzie I" first="Ian R." last="Mackenzie">Ian R. Mackenzie</name><affiliation wicri:level="1"><nlm:aff id="aff7">Department of Pathology and Laboratory Medicine,<institution>University of British Columbia</institution>, Vancouver, BC,<country>Canada</country> V5Z 1M9</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cashman, Neil R" sort="Cashman, Neil R" uniqKey="Cashman N" first="Neil R." last="Cashman">Neil R. Cashman</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease, is associated with mutation and misfolding of the Cu/Zn superoxide dismutase (SOD1) protein. Prior studies found that mutant misfolded SOD1 can convert wild-type (WT) SOD1 to a misfolded form inside living cells in a prion-like fashion. We now report that misfolded WT SOD1 can be transmitted from cell to cell, and that propagated protein misfolding can be perpetuated. Misfolded SOD1 transmission between cells can be mediated through release and uptake of protein aggregates or via small membrane-bounded transport vesicles called exosomes. These mechanisms may help explain why sporadic ALS, without a known genetic cause, can spread systematically from region to region in a progressive manner.</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="iso-abbrev">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">24550511</article-id><article-id pub-id-type="pmc">3948312</article-id><article-id pub-id-type="publisher-id">201312245</article-id><article-id pub-id-type="doi">10.1073/pnas.1312245111</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Neuroscience</subject></subj-group></subj-group></article-categories><title-group><article-title>Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms</article-title><alt-title alt-title-type="short">Intercellular propagated misfolding of SOD1</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Grad</surname><given-names>Leslie I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yerbury</surname><given-names>Justin J.</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Turner</surname><given-names>Bradley J.</given-names></name><xref ref-type="aff" rid="aff4"><sup>c</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guest</surname><given-names>William C.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pokrishevsky</surname><given-names>Edward</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>O’Neill</surname><given-names>Megan A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yanai</surname><given-names>Anat</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Silverman</surname><given-names>Judith M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zeineddine</surname><given-names>Rafaa</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Corcoran</surname><given-names>Lisa</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kumita</surname><given-names>Janet R.</given-names></name><xref ref-type="aff" rid="aff6"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Luheshi</surname><given-names>Leila M.</given-names></name><xref ref-type="aff" rid="aff6"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yousefi</surname><given-names>Masoud</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Coleman</surname><given-names>Bradley M.</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hill</surname><given-names>Andrew F.</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Plotkin</surname><given-names>Steven S.</given-names></name><xref ref-type="aff" rid="aff2"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mackenzie</surname><given-names>Ian R.</given-names></name><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cashman</surname><given-names>Neil R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1"><sup>a</sup>Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, BC,<country>Canada</country> V6T 2B5;</aff><aff id="aff3"><sup>b</sup>Illawarra Health and Medical Research Institute,<institution>University of Wollongong</institution>, Wollongong, NSW 2522,<country>Australia</country>;</aff><aff id="aff4"><sup>c</sup>Florey Institute of Neuroscience and Mental Health and</aff><aff id="aff5"><sup>e</sup>Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute,<institution>University of Melbourne</institution>, Parkville, VIC 3010,<country>Australia</country>;</aff><aff id="aff6"><sup>d</sup>Department of Chemistry,<institution>University of Cambridge</institution>, Cambridge CB2 1EW,<country>United Kingdom</country>;</aff><aff id="aff2"><sup>f</sup>Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada V6T 1Z1; and</aff><aff id="aff7"><sup>g</sup>Department of Pathology and Laboratory Medicine,<institution>University of British Columbia</institution>, Vancouver, BC,<country>Canada</country> V5Z 1M9</aff></contrib-group><author-notes><corresp id="cor1"><sup>2</sup>To whom correspondence should be addressed. E-mail: <email>neil.cashman@vch.ca</email>.</corresp><fn fn-type="edited-by"><p>Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved January 28, 2014 (received for review June 27, 2013)</p></fn><fn fn-type="con"><p>Author contributions: L.I.G., J.J.Y., B.J.T., and N.R.C. designed research; L.I.G., J.J.Y., B.J.T., W.C.G., E.P., M.A.O., A.Y., J.M.S., R.Z., L.C., J.R.K., L.M.L., B.M.C., and I.R.M. performed research; N.R.C. contributed new reagents/analytic tools; L.I.G., J.J.Y., B.J.T., W.C.G., E.P., M.A.O., A.Y., J.M.S., M.Y., B.M.C., A.F.H., S.S.P., I.R.M., and N.R.C. analyzed data; and L.I.G., J.J.Y., B.J.T., W.C.G., A.F.H., and N.R.C. wrote the paper.</p></fn><fn fn-type="equal" id="fn1"><p><sup>1</sup>L.I.G., J.J.Y., and B.J.T. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>4</day><month>3</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>18</day><month>2</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>18</day><month>2</month><year>2014</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>111</volume><issue>9</issue><fpage>3620</fpage><lpage>3625</lpage><permissions><license license-type="open-access"><license-p>Freely available online through the PNAS open access option.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201312245.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease, is associated with mutation and misfolding of the Cu/Zn superoxide dismutase (SOD1) protein. Prior studies found that mutant misfolded SOD1 can convert wild-type (WT) SOD1 to a misfolded form inside living cells in a prion-like fashion. We now report that misfolded WT SOD1 can be transmitted from cell to cell, and that propagated protein misfolding can be perpetuated. Misfolded SOD1 transmission between cells can be mediated through release and uptake of protein aggregates or via small membrane-bounded transport vesicles called exosomes. These mechanisms may help explain why sporadic ALS, without a known genetic cause, can spread systematically from region to region in a progressive manner.</p></abstract><abstract><p>Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5–10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-to-cell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.</p></abstract><kwd-group><kwd>protein misfolding</kwd><kwd>intercellular transmission</kwd><kwd>prion-like</kwd><kwd>disease-specific epitope</kwd></kwd-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc><affiliations><list><country><li>Australie</li><li>Canada</li><li>Royaume-Uni</li></country></list><tree><noCountry><name sortKey="Turner, Bradley J" sort="Turner, Bradley J" uniqKey="Turner B" first="Bradley J." last="Turner">Bradley J. Turner</name></noCountry><country name="Canada"><noRegion><name sortKey="Grad, Leslie I" sort="Grad, Leslie I" uniqKey="Grad L" first="Leslie I." last="Grad">Leslie I. Grad</name></noRegion><name sortKey="Cashman, Neil R" sort="Cashman, Neil R" uniqKey="Cashman N" first="Neil R." last="Cashman">Neil R. Cashman</name><name sortKey="Guest, William C" sort="Guest, William C" uniqKey="Guest W" first="William C." last="Guest">William C. Guest</name><name sortKey="Mackenzie, Ian R" sort="Mackenzie, Ian R" uniqKey="Mackenzie I" first="Ian R." last="Mackenzie">Ian R. Mackenzie</name><name sortKey="O Eill, Megan A" sort="O Eill, Megan A" uniqKey="O Eill M" first="Megan A." last="O Eill">Megan A. O Eill</name><name sortKey="Plotkin, Steven S" sort="Plotkin, Steven S" uniqKey="Plotkin S" first="Steven S." last="Plotkin">Steven S. Plotkin</name><name sortKey="Pokrishevsky, Edward" sort="Pokrishevsky, Edward" uniqKey="Pokrishevsky E" first="Edward" last="Pokrishevsky">Edward Pokrishevsky</name><name sortKey="Silverman, Judith M" sort="Silverman, Judith M" uniqKey="Silverman J" first="Judith M." last="Silverman">Judith M. Silverman</name><name sortKey="Yanai, Anat" sort="Yanai, Anat" uniqKey="Yanai A" first="Anat" last="Yanai">Anat Yanai</name><name sortKey="Yousefi, Masoud" sort="Yousefi, Masoud" uniqKey="Yousefi M" first="Masoud" last="Yousefi">Masoud Yousefi</name></country><country name="Australie"><noRegion><name sortKey="Yerbury, Justin J" sort="Yerbury, Justin J" uniqKey="Yerbury J" first="Justin J." last="Yerbury">Justin J. Yerbury</name></noRegion><name sortKey="Coleman, Bradley M" sort="Coleman, Bradley M" uniqKey="Coleman B" first="Bradley M." last="Coleman">Bradley M. Coleman</name><name sortKey="Corcoran, Lisa" sort="Corcoran, Lisa" uniqKey="Corcoran L" first="Lisa" last="Corcoran">Lisa Corcoran</name><name sortKey="Hill, Andrew F" sort="Hill, Andrew F" uniqKey="Hill A" first="Andrew F." last="Hill">Andrew F. Hill</name><name sortKey="Zeineddine, Rafaa" sort="Zeineddine, Rafaa" uniqKey="Zeineddine R" first="Rafaa" last="Zeineddine">Rafaa Zeineddine</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Kumita, Janet R" sort="Kumita, Janet R" uniqKey="Kumita J" first="Janet R." last="Kumita">Janet R. Kumita</name></noRegion><name sortKey="Luheshi, Leila M" sort="Luheshi, Leila M" uniqKey="Luheshi L" first="Leila M." last="Luheshi">Leila M. Luheshi</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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