Publication

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

Sin, O., de Jong, T., Mata-Cabana, A., Kudron, M., Zaini, M. A., Aprile, F. A., Seinstra, R. I., Stroo, E., Prins, R. W., Martineau, C. N., Wang, H. H., Hogewerf, W., Steinhof, A., Wanker, E. E., Vendruscolo, M., Calkhoven, C. F., Reinke, V., Guryev, V. & Nollen, E. A. A., 16-Mar-2017, In : Molecular Cell. 65, 6, p. 1096-1108 19 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1096-1108
Number of pages19
JournalMolecular Cell
Volume65
Issue number6
Publication statusPublished - 16-Mar-2017

    Keywords

  • ZINC-FINGER PROTEINS, DIFFERENTIAL EXPRESSION ANALYSIS, CAENORHABDITIS-ELEGANS, C.-ELEGANS, TRANSCRIPTION FACTORS, HUNTINGTON-DISEASE, GENE-EXPRESSION, POSTTRANSLATIONAL MODIFICATIONS, NEURODEGENERATIVE DISEASES, POLYGLUTAMINE PROTEIN

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