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Identification of an RNA polymerase III regulator linked to disease-associated protein aggregation

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Item Type:Article
Title:Identification of an RNA polymerase III regulator linked to disease-associated protein aggregation
Creators Name:Sin, O. and de Jong, T. and Mata-Cabana, A. and Kudron, M. and Zaini, M.A. and Aprile, F.A. and Seinstra, R.I. and Stroo, E. and Prins, R.W. and Martineau, C.N. and Wang, H.H. and Hogewerf, Wytse and Steinhof, A. and Wanker, E.E. and Vendruscolo, M. and Calkhoven, C.F. and Reinke, V. and Guryev, V. and Nollen, E.A.A.
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.
Keywords:Animal Disease Models, Binding Sites, Caenorhabditis elegans Proteins, Cell Nucleus, Cell Nucleus Active Transport, Cytosol, Genetic Promoter Regions, Genetic Transcription, Genetically Modified Animals, Neurodegenerative Diseases, Pathological Protein Aggregation, Peptides, Protein Aggregates, Protein Binding, RNA Interference, RNA Polymerase III, Small Untranslated RNA, Transcription Factors, Animals, Caenorhabditis elegans
Source:Molecular Cell
Publisher:Cell Press
Page Range:1096-1108
Date:16 March 2017
Official Publication:https://doi.org/10.1016/j.molcel.2017.02.022
PubMed:View item in PubMed

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