Metabolic Activity Determines Efficacy of Macroautophagic Clearance of Pathological Oligomeric α-Synuclein
Identifieur interne : 002082 ( Main/Exploration ); précédent : 002081; suivant : 002083Metabolic Activity Determines Efficacy of Macroautophagic Clearance of Pathological Oligomeric α-Synuclein
Auteurs : WAI HAUNG YU [États-Unis] ; Beatriz Dorado [États-Unis] ; Helen Yvette Figueroa [États-Unis] ; LILI WANG [États-Unis] ; Emmanuel Planel [Canada] ; Mark R. Cookson [États-Unis] ; Lorraine N. Clark [États-Unis] ; Karen E. Duff [États-Unis]Source :
- The American journal of pathology [ 0002-9440 ] ; 2009.
Descripteurs français
- Pascal (Inist)
English descriptors
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Abstract
Macroautophagy is an essential degradative pathway that can be induced to clear aggregated proteins, such as those found in Parkinson's disease and dementia with Lewy bodies, a form of Parkinsonism. This study found that both LC3-II and beclin were significantly increased in brains from humans with Dementia with Lewy bodies and transgenic mice overexpressing mutant α-synuclein, as compared with respective controls, suggesting that macroautophagy is induced to remove α-syn, particularly oligomeric or mutant forms. Aged mutant animals had higher autophagy biomarker levels relative to younger animals, suggesting that with aging, autophagy is less efficient and requires more stimulation to achieve the same outcome. Disruption of autophagy by RNA interference significantly increased α-syn oligomer accumulation in vitro , confirming the significance of autophagy in α-syn clearance. Finally, rotenone-induced α-syn aggregates were cleared following rapamycin stimulation of autophagy. Chronic rotenone exposure and commensurate reduction of metabolic activity limited the efficacy of rapamycin to promote autophagy, suggesting that cellular metabolism is critical for determining autophagic activity. Cumulatively, these fmdings support the concept that neuronal autophagy is essential for protein homeostasis and, in our system, reduction of autophagy increased the accumulation of potentially pathogenic α-synuclein oligomers. Aging and metabolic state were identified as important determinants of autophagic activity. This study provides therapeutic and pathological implications for both synucleinopathy and Parkinson's disease, identifying conditions in which autophagy may be insufficient to degrade α-syn aggregates.
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Cookson</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Gene Expression Unit, National Institutes of Health</s1><s2>Bethesda, Maryland</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Clark, Lorraine N" sort="Clark, Lorraine N" uniqKey="Clark L" first="Lorraine N." last="Clark">Lorraine N. Clark</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Taub Institute, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Pathology, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Center for Human Genetics, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation></author><author><name sortKey="Duff, Karen E" sort="Duff, Karen E" uniqKey="Duff K" first="Karen E." last="Duff">Karen E. Duff</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Taub Institute, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Pathology, Columbia University</s1><s2>New York, New York</s2><s3>USA</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region><settlement type="city">New York</settlement></placeName><orgName type="university">Université Columbia</orgName></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="2009">2009</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>Alpha-synuclein</term><term>Anatomic pathology</term><term>Biological activity</term><term>Clearance</term><term>Metabolism</term><term>Treatment efficiency</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Métabolisme</term><term>Activité biologique</term><term>Efficacité traitement</term><term>Clairance</term><term>Protéine acide</term><term>Alpha-synucléine</term><term>Anatomopathologie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Macroautophagy is an essential degradative pathway that can be induced to clear aggregated proteins, such as those found in Parkinson's disease and dementia with Lewy bodies, a form of Parkinsonism. This study found that both LC3-II and beclin were significantly increased in brains from humans with Dementia with Lewy bodies and transgenic mice overexpressing mutant α-synuclein, as compared with respective controls, suggesting that macroautophagy is induced to remove α-syn, particularly oligomeric or mutant forms. Aged mutant animals had higher autophagy biomarker levels relative to younger animals, suggesting that with aging, autophagy is less efficient and requires more stimulation to achieve the same outcome. Disruption of autophagy by RNA interference significantly increased α-syn oligomer accumulation in vitro , confirming the significance of autophagy in α-syn clearance. Finally, rotenone-induced α-syn aggregates were cleared following rapamycin stimulation of autophagy. Chronic rotenone exposure and commensurate reduction of metabolic activity limited the efficacy of rapamycin to promote autophagy, suggesting that cellular metabolism is critical for determining autophagic activity. Cumulatively, these fmdings support the concept that neuronal autophagy is essential for protein homeostasis and, in our system, reduction of autophagy increased the accumulation of potentially pathogenic α-synuclein oligomers. Aging and metabolic state were identified as important determinants of autophagic activity. This study provides therapeutic and pathological implications for both synucleinopathy and Parkinson's disease, identifying conditions in which autophagy may be insufficient to degrade α-syn aggregates.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Maryland</li><li>État de New York</li></region><settlement><li>New York</li></settlement><orgName><li>Université Columbia</li></orgName></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Wai Haung Yu" sort="Wai Haung Yu" uniqKey="Wai Haung Yu" last="Wai Haung Yu">WAI HAUNG YU</name></region><name sortKey="Clark, Lorraine N" sort="Clark, Lorraine N" uniqKey="Clark L" first="Lorraine N." last="Clark">Lorraine N. Clark</name><name sortKey="Clark, Lorraine N" sort="Clark, Lorraine N" uniqKey="Clark L" first="Lorraine N." last="Clark">Lorraine N. Clark</name><name sortKey="Clark, Lorraine N" sort="Clark, Lorraine N" uniqKey="Clark L" first="Lorraine N." last="Clark">Lorraine N. Clark</name><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. Cookson</name><name sortKey="Dorado, Beatriz" sort="Dorado, Beatriz" uniqKey="Dorado B" first="Beatriz" last="Dorado">Beatriz Dorado</name><name sortKey="Duff, Karen E" sort="Duff, Karen E" uniqKey="Duff K" first="Karen E." last="Duff">Karen E. Duff</name><name sortKey="Duff, Karen E" sort="Duff, Karen E" uniqKey="Duff K" first="Karen E." last="Duff">Karen E. Duff</name><name sortKey="Lili Wang" sort="Lili Wang" uniqKey="Lili Wang" last="Lili Wang">LILI WANG</name><name sortKey="Yvette Figueroa, Helen" sort="Yvette Figueroa, Helen" uniqKey="Yvette Figueroa H" first="Helen" last="Yvette Figueroa">Helen Yvette Figueroa</name></country><country name="Canada"><noRegion><name sortKey="Planel, Emmanuel" sort="Planel, Emmanuel" uniqKey="Planel E" first="Emmanuel" last="Planel">Emmanuel Planel</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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