Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted

The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to...

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Published in:	Nature communications Vol. 12; no. 1; p. 4272
Main Authors:	Mario Isas, J., Pandey, Nitin K., Xu, Hui, Teranishi, Kazuki, Okada, Alan K., Fultz, Ellisa K., Rawat, Anoop, Applebaum, Anise, Meier, Franziska, Chen, Jeannie, Langen, Ralf, Siemer, Ansgar B.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 13-07-2021 Nature Publishing Group Nature Portfolio
Subjects:	140/131 147/28 631/45/470/2284 631/57/2269 631/57/2272/2273 82/1 82/80 Domains Electron paramagnetic resonance Electron spin resonance Entanglement Fibrils Humanities and Social Sciences Huntingtin Huntington's disease Huntingtons disease multidisciplinary Neurodegenerative diseases NMR Nuclear magnetic resonance Polyglutamine diseases Polyproline Proline Protein interaction Proteins Science Science (multidisciplinary) Toxic diseases Toxicity Trinucleotide repeat diseases
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Summary:	The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease. Huntingtin exon-1 (HTTex1) consists of a N-terminal N17 domain, the disease causing polyQ domain and a C-terminal proline-rich domain (PRD). Here, the authors combine electron paramagnetic resonance (EPR), solid-state NMR with other biophysical method to characterise the structural differences of various HTTex1 fibril types with different toxicity and find that the dynamics and entanglement of the PRD domain differs among them and that the HTTex1 fibrils can be interconverted.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-24411-2