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

J. Mario Isas, Nitin K. Pandey, Hui Xu, Kazuki Teranishi, Alan K. Okada, Ellisa K. Fultz, Anoop Rawat, Anise Applebaum, Franziska Meier, Jeannie Chen, Ralf Langen () and Ansgar B. Siemer ()
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J. Mario Isas: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Nitin K. Pandey: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Hui Xu: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Kazuki Teranishi: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Alan K. Okada: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Ellisa K. Fultz: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Anoop Rawat: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Anise Applebaum: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Franziska Meier: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Jeannie Chen: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Ralf Langen: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California
Ansgar B. Siemer: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24411-2

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