Calpain-cleavage of α-synuclein : Connecting proteolytic processing to disease-linked aggregation
Identifieur interne : 002695 ( Main/Exploration ); précédent : 002694; suivant : 002696Calpain-cleavage of α-synuclein : Connecting proteolytic processing to disease-linked aggregation
Auteurs : Brian M. Dufty [États-Unis] ; Lisa R. Warner [États-Unis] ; Sheng T. Hou [Canada] ; Susan X. Jiang [Canada] ; Teresa Gomez-Isia [Espagne] ; Kristen M. Leenhouts [États-Unis] ; Julia T. Oxford [États-Unis] ; Mel B. Feany [États-Unis] ; Eliezer Masliah [États-Unis] ; Troy T. Rohn [États-Unis]Source :
- The American journal of pathology [ 0002-9440 ] ; 2007.
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Abstract
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs are aggregates of α-synuclein (a-Syn), and although it is now recognized that α-Syn is the major building block for these toxic filaments, the mechanism of how this occurs remains unknown. In the present study, we demonstrate that proteolytic processing of α-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a β-sheet structure. To determine whether calpain-cleavage of α-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to α-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved α-Syn was evident in mouse models of cerebral ischemia and PD and in a Drosophila model of PD. In the human PD and DLB brain, calpain-cleaved α-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved α-Syn fragments identified within LBs colocalized with activated calpain in neurons of the PD and DLB brains. These findings suggest that calpain I may participate in the disease-linked aggregation of α-Syn in various α-synucleinopathies.
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Dufty</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Biology, Boise State University</s1><s2>Boise, Idaho</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Idaho</region></placeName></affiliation></author><author><name sortKey="Warner, Lisa R" sort="Warner, Lisa R" uniqKey="Warner L" first="Lisa R." last="Warner">Lisa R. Warner</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Biology, Boise State University</s1><s2>Boise, Idaho</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Idaho</region></placeName></affiliation></author><author><name sortKey="Hou, Sheng T" sort="Hou, Sheng T" uniqKey="Hou S" first="Sheng T." last="Hou">Sheng T. Hou</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Experimental NeuroTherapeutics Laboratoly, National Research Council Institute for Biological Sciences, National Research Council Canada</s1><s2>Ottawa, Ontario</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Jiang, Susan X" sort="Jiang, Susan X" uniqKey="Jiang S" first="Susan X." last="Jiang">Susan X. Jiang</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Experimental NeuroTherapeutics Laboratoly, National Research Council Institute for Biological Sciences, National Research Council Canada</s1><s2>Ottawa, Ontario</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Gomez Isia, Teresa" sort="Gomez Isia, Teresa" uniqKey="Gomez Isia T" first="Teresa" last="Gomez-Isia">Teresa Gomez-Isia</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Unidad de Memoria, Servicio de Neurologia, Hospital Santa Creu i Sant Pau</s1><s2>Barcelona</s2><s3>ESP</s3><sZ>5 aut.</sZ></inist:fA14><country>Espagne</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Leenhouts, Kristen M" sort="Leenhouts, Kristen M" uniqKey="Leenhouts K" first="Kristen M." last="Leenhouts">Kristen M. Leenhouts</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Biology, Boise State University</s1><s2>Boise, Idaho</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Idaho</region></placeName></affiliation></author><author><name sortKey="Oxford, Julia T" sort="Oxford, Julia T" uniqKey="Oxford J" first="Julia T." last="Oxford">Julia T. Oxford</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Biology, Boise State University</s1><s2>Boise, Idaho</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Idaho</region></placeName></affiliation></author><author><name sortKey="Feany, Mel B" sort="Feany, Mel B" uniqKey="Feany M" first="Mel B." last="Feany">Mel B. Feany</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Pathology, Brigham and Women's Hospital, Harvard Medical School</s1><s2>Boston, Massachusetts</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Masliah, Eliezer" sort="Masliah, Eliezer" uniqKey="Masliah E" first="Eliezer" last="Masliah">Eliezer Masliah</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Department of Neurosciences and Neuropathology, University of California, San Diego</s1><s2>La Jolla, California</s2><s3>USA</s3><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Rohn, Troy T" sort="Rohn, Troy T" uniqKey="Rohn T" first="Troy T." last="Rohn">Troy T. Rohn</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Biology, Boise State University</s1><s2>Boise, Idaho</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Idaho</region></placeName></affiliation></author></analytic><series><title level="j" type="main">The American journal of pathology</title><title level="j" type="abbreviated">Am. j. pathol.</title><idno type="ISSN">0002-9440</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">The American journal of pathology</title><title level="j" type="abbreviated">Am. j. pathol.</title><idno type="ISSN">0002-9440</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acidic protein</term><term>Aggregation</term><term>Anatomic pathology</term><term>Calpain</term><term>Cleavage</term><term>α synuclein</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Calpain</term><term>Clivage</term><term>Protéine acide</term><term>Agrégation</term><term>Anatomopathologie</term><term>Synucléine-α</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs are aggregates of α-synuclein (a-Syn), and although it is now recognized that α-Syn is the major building block for these toxic filaments, the mechanism of how this occurs remains unknown. In the present study, we demonstrate that proteolytic processing of α-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a β-sheet structure. To determine whether calpain-cleavage of α-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to α-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved α-Syn was evident in mouse models of cerebral ischemia and PD and in a Drosophila model of PD. In the human PD and DLB brain, calpain-cleaved α-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved α-Syn fragments identified within LBs colocalized with activated calpain in neurons of the PD and DLB brains. These findings suggest that calpain I may participate in the disease-linked aggregation of α-Syn in various α-synucleinopathies.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Espagne</li><li>États-Unis</li></country><region><li>Californie</li><li>Catalogne</li><li>Idaho</li><li>Massachusetts</li></region><settlement><li>Barcelone</li></settlement></list><tree><country name="États-Unis"><region name="Idaho"><name sortKey="Dufty, Brian M" sort="Dufty, Brian M" uniqKey="Dufty B" first="Brian M." last="Dufty">Brian M. Dufty</name></region><name sortKey="Feany, Mel B" sort="Feany, Mel B" uniqKey="Feany M" first="Mel B." last="Feany">Mel B. Feany</name><name sortKey="Leenhouts, Kristen M" sort="Leenhouts, Kristen M" uniqKey="Leenhouts K" first="Kristen M." last="Leenhouts">Kristen M. Leenhouts</name><name sortKey="Masliah, Eliezer" sort="Masliah, Eliezer" uniqKey="Masliah E" first="Eliezer" last="Masliah">Eliezer Masliah</name><name sortKey="Oxford, Julia T" sort="Oxford, Julia T" uniqKey="Oxford J" first="Julia T." last="Oxford">Julia T. Oxford</name><name sortKey="Rohn, Troy T" sort="Rohn, Troy T" uniqKey="Rohn T" first="Troy T." last="Rohn">Troy T. Rohn</name><name sortKey="Warner, Lisa R" sort="Warner, Lisa R" uniqKey="Warner L" first="Lisa R." last="Warner">Lisa R. Warner</name></country><country name="Canada"><noRegion><name sortKey="Hou, Sheng T" sort="Hou, Sheng T" uniqKey="Hou S" first="Sheng T." last="Hou">Sheng T. Hou</name></noRegion><name sortKey="Jiang, Susan X" sort="Jiang, Susan X" uniqKey="Jiang S" first="Susan X." last="Jiang">Susan X. Jiang</name></country><country name="Espagne"><region name="Catalogne"><name sortKey="Gomez Isia, Teresa" sort="Gomez Isia, Teresa" uniqKey="Gomez Isia T" first="Teresa" last="Gomez-Isia">Teresa Gomez-Isia</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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