title: Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation.
abstract: Protein aggregation is associated with age-related neurodegenerative disorders, such as Alzheimer's and polyglutamine diseases. As a causal relationship between protein aggregation and neurodegeneration remains elusive, understanding the cellular mechanisms regulating protein aggregation will help develop future treatments. To identify such mechanisms, we conducted a forward genetic screen in a C. elegans model of polyglutamine aggregation and identified the protein MOAG-2/LIR-3 as a driver of protein aggregation. In the absence of polyglutamine, MOAG-2/LIR-3 regulates the RNA polymerase III-associated transcription of small non-coding RNAs. This regulation is lost in the presence of polyglutamine, which mislocalizes MOAG-2/LIR-3 from the nucleus to the cytosol. We then show biochemically that MOAG-2/LIR-3 can also catalyze the aggregation of polyglutamine-expanded huntingtin. These results suggest that polyglutamine can induce an aggregation-promoting activity of MOAG-2/LIR-3 in the cytosol. The concept that certain aggregation-prone proteins can convert other endogenous proteins into drivers of aggregation and toxicity adds to the understanding of how cellular homeostasis can be deteriorated in protein misfolding diseases.
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands; Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
authors.forename: Olga
authors.initials: O
authors.lastname: Sin
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Tristan
authors.initials: T
authors.lastname: de Jong
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Mata-Cabana
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kudron
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Mohamad Amr
authors.initials: MA
authors.lastname: Zaini
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Aprile
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Renée I
authors.initials: RI
authors.lastname: Seinstra
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Stroo
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Roméo Willinge
authors.initials: RW
authors.lastname: Prins
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Céline N
authors.initials: CN
authors.lastname: Martineau
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Hai Hui
authors.initials: HH
authors.lastname: Wang
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Wytse
authors.initials: W
authors.lastname: Hogewerf
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Steinhof
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
authors.forename: Cornelis F
authors.initials: CF
authors.lastname: Calkhoven
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Reinke
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands. Electronic address: v.guryev@umcg.nl.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands. Electronic address: e.a.a.nollen@umcg.nl.
authors.forename: Ellen A A
authors.initials: EA
authors.lastname: Nollen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D034622:RNA Interference; D012320:RNA Polymerase III / Q000235:genetics / Q000378:metabolism*; D058727:RNA, Small Untranslated / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D029742:Caenorhabditis elegans Proteins; C000622383:LIR-3 protein, C elegans; D010455:Peptides; D066329:Protein Aggregates; D058727:RNA, Small Untranslated; D014157:Transcription Factors; C097188:polyglutamine; D012320:RNA Polymerase III
keywords: C. elegans; MOAG-2/LIR-3; RNA polymerase III; non-coding RNA; polyglutamine; protein aggregation; protein homeostasis; protein quality control; snoRNA; tRNA