1. Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation.
- Author
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Sin O, de Jong T, Mata-Cabana A, Kudron M, Zaini MA, Aprile FA, Seinstra RI, Stroo E, Prins RW, Martineau CN, Wang HH, Hogewerf W, Steinhof A, Wanker EE, Vendruscolo M, Calkhoven CF, Reinke V, Guryev V, and Nollen EA
- Subjects
- Active Transport, Cell Nucleus, Animals, Animals, Genetically Modified, Binding Sites, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins genetics, Cell Nucleus enzymology, Cytosol enzymology, Disease Models, Animal, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Promoter Regions, Genetic, Protein Binding, RNA Interference, RNA Polymerase III genetics, RNA, Small Untranslated genetics, RNA, Small Untranslated metabolism, Transcription Factors genetics, Transcription, Genetic, Caenorhabditis elegans enzymology, Caenorhabditis elegans Proteins metabolism, Neurodegenerative Diseases enzymology, Peptides metabolism, Protein Aggregates, Protein Aggregation, Pathological, RNA Polymerase III metabolism, Transcription Factors metabolism
- 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., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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