Stick-slip unfolding favors self-association of expanded HTT mRNA

Brett M. O’Brien, Roumita Moulick, Gabriel Jiménez-Avalos, Nandakumar Rajasekaran, Christian M. Kaiser () and Sarah A. Woodson ()
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Brett M. O’Brien: Johns Hopkins University
Roumita Moulick: Johns Hopkins University
Gabriel Jiménez-Avalos: Johns Hopkins University
Nandakumar Rajasekaran: Johns Hopkins University
Christian M. Kaiser: Johns Hopkins University
Sarah A. Woodson: Johns Hopkins University

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract In Huntington’s Disease (HD) and related disorders, expansion of CAG trinucleotide repeats produces a toxic gain of function in affected neurons. Expanded huntingtin (expHTT) mRNA forms aggregates that sequester essential RNA binding proteins, dysregulating mRNA processing and translation. The physical basis of RNA aggregation has been difficult to disentangle owing to the heterogeneous structure of the CAG repeats. Here, we probe the folding and unfolding pathways of expHTT mRNA using single-molecule force spectroscopy. Whereas normal HTT mRNAs unfold reversibly and cooperatively, expHTT mRNAs with 20 or 40 CAG repeats slip and unravel non-cooperatively at low tension. Slippage of CAG base pairs is punctuated by concerted rearrangement of adjacent CCG trinucleotides, trapping partially folded structures that readily base pair with another RNA strand. We suggest that the conformational entropy of the CAG repeats, combined with stable CCG base pairs, creates a stick-slip behavior that explains the aggregation propensity of expHTT mRNA.

Date: 2024
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DOI: 10.1038/s41467-024-52764-x

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