Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/37404
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dc.contributor.authorPimenta de Castro, I.-
dc.contributor.authorCosta, A. C.-
dc.contributor.authorLam, D.-
dc.contributor.authorTufi, R.-
dc.contributor.authorFedele, V.-
dc.contributor.authorMoisoi, N.-
dc.contributor.authorDinsdale, D.-
dc.contributor.authorDeas, E.-
dc.contributor.authorLoh, S. H.-
dc.contributor.authorMartins, L. Miguel-
dc.date.accessioned2016-04-20T10:52:46Z-
dc.date.available2016-04-20T10:52:46Z-
dc.date.issued2012-02-03-
dc.identifier.citationCell Death and Differentiation, 2012, 19 (8), pp. 1308-1316en
dc.identifier.issn1350-9047-
dc.identifier.urihttp://www.nature.com/cdd/journal/v19/n8/full/cdd20125a.htmlen
dc.identifier.urihttp://hdl.handle.net/2381/37404-
dc.description.abstractProtein misfolding has a key role in several neurological disorders including Parkinson's disease. Although a clear mechanism for such proteinopathic diseases is well established when aggregated proteins accumulate in the cytosol, cell nucleus, endoplasmic reticulum and extracellular space, little is known about the role of protein aggregation in the mitochondria. Here we show that mutations in both human and fly PINK1 result in higher levels of misfolded components of respiratory complexes and increase in markers of the mitochondrial unfolded protein response. Through the development of a genetic model of mitochondrial protein misfolding employing Drosophila melanogaster, we show that the in vivo accumulation of an unfolded protein in mitochondria results in the activation of AMP-activated protein kinase-dependent autophagy and phenocopies of pink1 and parkin mutants. Parkin expression acts to clear mitochondria with enhanced levels of misfolded proteins by promoting their autophagic degradation in vivo, and refractory to Sigma P (ref(2)P), the Drosophila orthologue of mammalian p62, is a critical downstream effector of this quality control pathway. We show that in flies, a pathway involving pink1, parkin and ref(2)P has a role in the maintenance of a viable pool of cellular mitochondria by promoting organellar quality control.en
dc.language.isoenen
dc.publisherNature Publishing Group for Congregazione dei Figli dell'Immacolata Concezione (CFIC), Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Dermopatico dell'Immacolata (IDI-IRCCS)en
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/22301916-
dc.rightsCopyright © 2012, the authors. This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/en
dc.subjectAnimalsen
dc.subjectAnimals, Genetically Modifieden
dc.subjectDrosophila Proteinsen
dc.subjectDrosophila melanogasteren
dc.subjectHEK293 Cellsen
dc.subjectHumansen
dc.subjectMitochondriaen
dc.subjectMitochondrial Proteinsen
dc.subjectProtein Foldingen
dc.subjectProtein Transporten
dc.subjectProtein-Serine-Threonine Kinasesen
dc.subjectUbiquitin-Protein Ligasesen
dc.titleGenetic analysis of mitochondrial protein misfolding in Drosophila melanogasteren
dc.typeJournal Articleen
dc.identifier.doi10.1038/cdd.2012.5-
dc.identifier.eissn1476-5403-
dc.identifier.piicdd20125-
dc.description.statusPeer-revieweden
dc.description.versionPublisher Versionen
dc.type.subtypeJournal Article;Research Support, Non-U.S. Gov't-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGYen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departmentsen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biologyen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Old Departments Pre 01 Aug 2015en
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Old Departments Pre 01 Aug 2015/Department of Cell Physiology and Pharmacology (Pre 01 Aug 2015)en
dc.dateaccepted2012-01-09-
Appears in Collections:Published Articles, MRC Toxicology Unit

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