RNA Phase Transitions in Repeat Expansion Disorders

By Ankur Jain, R. Vale. Nature, 2017

795 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b1e4e654001727b84f56146363f1c70ebdf9061b

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Citations in the corpus

Liquid phase condensation in cell physiology and disease (2017, background): “Moreover, recent work supports the idea that the phase behavior of RNA itself is important and could play a role in neurodegenerative diseases associated with trinucleotide RNA repeats (73).”
Liquid-Liquid Phase Separation in Disease. (2019, background): “Blocking the formation of such aberrant condensates by inhibitors that disrupt RNA gelation (76) may be a viable strategy for treating repeat expansion disorders.”
Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions (2020, background): “Sufficiently long TNRE can form foci in vivo through phase separation [16].”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “Interestingly, such repeat RNAs can themselves phase separate through multivalent base pairing, mimicking the foci observed in patients [65].”
Alternative RNA Conformations: Companion or Combatant (2022, background): “It has been shown that in case of neurological diseases, the formation of RNA granules can be inhibited by means of RNA intercalating agents to stabilize or destabilize particular RNA secondary structures in a conformational ensemble [73].”