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April 13, 2018

Hardening of the RNA Condensates May Solidify Neurodegeneration

Membraneless compartments in the cell may form if RNA molecules have the right shapes to expose complementary base sequences and promote RNA-RNA interactions, which may support a transition to a liquid-like phase consisting of RNA-protein condensates. By assuming different shapes, RNA molecules may promote the formation and coexistence of the diverse array of RNA-rich liquid compartments found in a single cell. In this image, distinct RNA-protein condensates are shown. Scale bar: 10 um. [UNC-Chapel Hill]

  • A living cell’s liquid fraction must have just the right amount of fluidity. It can’t be too much of a random soup, or else chemical partners might take too long to find each other. And it can’t be too ordered, or else temporary aggregates might last too long, potentially contributing to protein aggregation diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as amyotrophic lateral sclerosis (ALS) and prion diseases.

    In the living cell, randomness and order in the liquid fraction may be accomplished by simple phase separations, of the sort that occur between oil and water. The possibility that phase transitions could create membrane-free intracellular compartments has intrigued many scientists over the past decade. Such phase transitions have been observed. Protein and RNA molecules do indeed condense into liquid-like droplets. Yet mechanistic details have proven a bit too slippery for scientists to grasp.

    To get a firmer hold of liquid-like condensates, scientists affiliated with the University of North Carolina and the Marine Biological Laboratory focused on the secondary or three-dimensional structures that RNA may form. These scientists have found that RNA molecules may segregate into different droplets, or congregate in the same droplets, depending on whether the molecules expose their complementary base sequences to each other.

    Details appeared April 12 in the journal Science, in an article entitled “mRNA Structure Determines Specificity of a PolyQ-Driven Phase Separation.” The article outlines a mechanism that can explain how secondary structure allows mRNAs to self-associate. This mechanism, the article’s authors suggest, determines whether an mRNA is recruited to or excluded from liquid compartments.

  • The fungus, Ashbya gossypii, contains many nuclei and hyphae in the same cytoplasm. [UNC-Chapel Hill]
  • “The polyQ-protein Whi3 induces conformational changes in RNA structure and generates distinct molecular fluctuations depending on the RNA sequence,” wrote the article’s authors. “These data support a model in which structure-based, RNA-RNA interactions promote assembly of distinct droplets and protein-driven, conformational dynamics of the RNA maintain this identity.”

    These findings reveal a selective mechanism for forming RNA–protein condensates—which scientists are seeing everywhere in cells but whose function is still unclear. The condensates may serve as "crucibles" for enhancing biological reactions by concentrating specific molecules together. Or they may sequester molecules that the cell doesn't need for a particular biological process.

    The findings may also inform our understanding of protein-aggregation and neurodegenerative diseases. Liquid droplets within cells occur under normal, healthy conditions, but through mutations, aging or stress, they can become more aggregated or harden, and then they are irreversible and won't dissolve. Eventually, researchers may understand how the right components within a cell can get recruited to droplets, so that cells can potentially avoid that transition to an aberrant, solid state.

    "The inside of a cell is not random soup,” insisted Amy Gladfelter, Ph.D., associate professor of biology at the University of North Carolina at Chapel Hill. “It has spatial structure to it. Certain things need to be near each other, so they can work together. "We found that the molecules of RNA are recognizing each other to join together into the same cellular droplets because of very specific and complex shapes that the RNA molecules take on."

    "RNA molecules will end up in different droplets if their secondary structures are shielding any complementarity. But with the RNAs that condense into the same droplet, their complementary sequences are really exposed, so they can find each other and base pair to make a higher-order interaction."

    Dr. Gladfelter has previously demonstrated in fungus that it's critical that the cell undergo a liquid–liquid phase separation in order for two different biological process to occur. "But we need more examples of where it really matters for cell function," Gladfelter noted, adding that the field needs evidence "that this is not just something that proteins and RNAs can do, but that nature has selected for it."

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