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

Publication date: Oct 09, 2024

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.

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Concepts	Keywords
Concerted	Base Pairing
Huntingtin	HTT protein, human
Mrnas	Humans
Spectroscopy	Huntingtin Protein
Toxic	Huntingtin Protein
	Huntington Disease
	Nucleic Acid Conformation
	RNA Folding
	RNA, Messenger
	RNA, Messenger
	Single Molecule Imaging
	Trinucleotide Repeat Expansion

Semantics

Type	Source	Name
disease	MESH	Huntington’s Disease
pathway	REACTOME	Translation
drug	DRUGBANK	Esomeprazole
drug	DRUGBANK	Proline
drug	DRUGBANK	Pirenzepine
drug	DRUGBANK	Gold
disease	MESH	ramp
drug	DRUGBANK	Potassium Chloride
drug	DRUGBANK	Altretamine
drug	DRUGBANK	Pentaerythritol tetranitrate
drug	DRUGBANK	Thiocolchicoside
disease	MESH	dissociation
disease	MESH	trinucleotide repeat expansion
pathway	REACTOME	Digestion
drug	DRUGBANK	Water
drug	DRUGBANK	Edetic Acid
drug	DRUGBANK	Tretamine
drug	DRUGBANK	Oxygen
drug	DRUGBANK	Aspartame
pathway	KEGG	Huntington disease
disease	MESH	pathogenesis
disease	MESH	myotonic dystrophy
disease	MESH	Death
drug	DRUGBANK	Coenzyme M
drug	DRUGBANK	Guanosine
drug	DRUGBANK	ATP
pathway	KEGG	Ribosome
pathway	REACTOME	Reproduction