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

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Mar 18

PMID 28306505

Citations 7

Authors

Olga Sin

Tristan de Jong

Alejandro Mata-Cabana

Michelle Kudron

Mohamad Amr Zaini

Francesco A Aprile

Renee I Seinstra

Esther Stroo

Romeo Willinge Prins

Celine N Martineau

Hai Hui Wang

Wytse Hogewerf

Anne Steinhof

Erich E Wanker

Michele Vendruscolo

Cornelis F Calkhoven

Valerie Reinke

Victor Guryev

Ellen A A Nollen

Affiliations

Soon will be listed here.

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.

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