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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Sin, Olga 
de Jong, Tristan 
Mata-Cabana, Alejandro 
Kudron, Michelle 
Zaini, Mohamad Amr 

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.

Description

Keywords

C. elegans, MOAG-2/LIR-3, RNA polymerase III, non-coding RNA, polyglutamine, protein aggregation, protein homeostasis, protein quality control, snoRNA, tRNA, Active Transport, Cell Nucleus, Animals, Animals, Genetically Modified, Binding Sites, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Nucleus, Cytosol, Disease Models, Animal, Neurodegenerative Diseases, Peptides, Promoter Regions, Genetic, Protein Aggregates, Protein Aggregation, Pathological, Protein Binding, RNA Interference, RNA Polymerase III, RNA, Small Untranslated, Transcription Factors, Transcription, Genetic

Journal Title

Mol Cell

Conference Name

Journal ISSN

1097-2765
1097-4164

Volume Title

65

Publisher

Elsevier BV