Polyglutamine makes the switch

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Science Signaling  28 Mar 2017:
Vol. 10, Issue 472, eaan3006
DOI: 10.1126/scisignal.aan3006

In worms, a regulator of noncoding RNA directly catalyzes formation of toxic protein aggregates in the presence of polyglutamine.

Many neurodegenerative disorders are associated with protein aggregation in the brain, but the underlying connection between aggregate formation and pathology is incompletely understood. Huntington’s disease is caused by heritable expansion of CAG repeats, which encode polyglutamine proteins. The progression of Huntington’s pathology is associated with increasing formation of polyglutamine aggregates. In a Caenorhabditis elegans protein aggregation model, Sin et al. identified a regulatory protein that, in the presence of polyglutamine, switched from regulating transcription to promoting polyglutamine aggregation. Worms expressing Q40, a 40-residue polyglutamine chain that forms aggregates, were screened for mutations that reduced the amount of aggregation. Polyglutamine aggregation was reduced by 50% in worms with a mutation in moag-2 (also known as lir-3), which encodes a zinc-finger protein predicted to be a transcription factor. Chromatin immunoprecipitation with sequencing (ChIP-seq) revealed that FLAG-tagged MOAG-2/LIR-3 preferentially bound to transcription start sites of genes encoding tRNAs, rRNAs, small nucleolar RNAs, and small nuclear RNAs (snoRNAs and snRNAs), and was associated with motifs recognized by RNA polymerase III. Indeed, mutations in moag-2/lir-3 (in the absence of polyglutamine) reduced the expression of small noncoding RNAs but not that of any protein-coding genes. Furthermore, MOAG-2/LIR-3 coimmunoprecipitated with RNA polymerase III but not RNA polymerase II. Neither RNAi knockdown of individual components of the RNA polymerase III complex nor knockdown of proteins involved in noncoding RNA processing affected polyglutamine aggregation in Q40 worms, suggesting that MOAG-2/LIR-3 promoted polyglutamine aggregation independently of its role in regulating noncoding RNA. The expression of snRNAs, snoRNAs, and tRNAs (but not of protein-coding genes) was lower in Q40 worms than in wild-type worms, regardless of whether moag-2/lir-3 was wild-type or mutated, suggesting that the presence of polyglutamine suppressed small noncoding RNA transcription. Overexpressing MOAG-2/LIR-3 in Q40 worms resulted in age-related impairments in mobility, whereas it improved mobility in older worms that were not expressing polyglutamine. In vitro, purified recombinant MOAG-2/LIR-3 induced amyloid formation in a disease-associated form of huntingtin protein. Tagged MOAG-2/LIR-3 localized to the nucleus in wild-type worms, but it localized to the cytosol in Q40 worms. Together, these results suggest that polyglutamine protein retains MOAG-2/LIR-3 in the cytosol, resulting in polyglutamine aggregate formation and reduced expression of small regulatory RNAs. This study adds to evidence that the toxicity of protein aggregates in neurodegenerative diseases may be due to their interference with protein trafficking to the nucleus.

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