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Mol Cell. 2017 Mar 16;65(6):1096-1108.e6. doi: 10.1016/j.molcel.2017.02.022.

Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation.

Author information

1
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.
2
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, 9700 AD Groningen, the Netherlands.
3
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
5
Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
6
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.
7
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.

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:

C. elegans; MOAG-2/LIR-3; RNA polymerase III; non-coding RNA; polyglutamine; protein aggregation; protein homeostasis; protein quality control; snoRNA; tRNA

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PMID:
28306505
PMCID:
PMC5364375
DOI:
10.1016/j.molcel.2017.02.022
[Indexed for MEDLINE]
Free PMC Article

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