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Nature. 2017 Jun 8;546(7657):243-247. doi: 10.1038/nature22386. Epub 2017 May 31.

RNA phase transitions in repeat expansion disorders.

Jain A1,2, Vale RD1,2.

Author information

1
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA.
2
Howard Hughes Medical Institute Summer Institute, Marine Biological Laboratory, Woods Hole, Massachusetts 02543, USA.

Abstract

Expansions of short nucleotide repeats produce several neurological and neuromuscular disorders including Huntington disease, muscular dystrophy, and amyotrophic lateral sclerosis. A common pathological feature of these diseases is the accumulation of the repeat-containing transcripts into aberrant foci in the nucleus. RNA foci, as well as the disease symptoms, only manifest above a critical number of nucleotide repeats, but the molecular mechanism governing foci formation above this characteristic threshold remains unresolved. Here we show that repeat expansions create templates for multivalent base-pairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in the diseases. In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Analogous to protein aggregation disorders, our results suggest that the sequence-specific gelation of RNAs could be a contributing factor to neurological disease.

PMID:
28562589
PMCID:
PMC5555642
DOI:
10.1038/nature22386
[Indexed for MEDLINE]
Free PMC Article

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