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Volume 26
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10.3390/ijms26178162
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Coiled-Coil Structures Mediate the Intercellular Propagation of Huntingtin

by
Marco Bosica
1,
Chiara Grasselli
1,
Andrea Panfili
1,
Franca Orsini
1 and
Luana Fioriti
1,2,*
1
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy
2
Department of Cell Biology and Pathology, Columbia University, New York, NY 10032, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(17), 8162; https://doi.org/10.3390/ijms26178162
Submission received: 23 May 2025 / Revised: 7 August 2025 / Accepted: 20 August 2025 / Published: 22 August 2025
(This article belongs to the Section Biochemistry)
Versions Notes

Abstract

Huntington’s Disease (HD) originates from the expansion of a polyglutamine (PolyQ) tract in the huntingtin protein (Htt), which can assume a coiled-coil fold (Cc). We previously found that Cc structures mediate the aggregation and toxicity of polyQ Htt. Since polyQ Htt aggregates were previously found to be internalized by cells, here we hypothesize that Cc structures might be implicated in the intercellular propagation of Htt aggregates. To test this hypothesis, we performed experiments using human cell lines expressing Htt proteins with different probabilities to acquire a Cc fold. We found that Htt with reduced Cc structures were released significantly less compared to Htt with intact Cc structures. We also found that Cc structures mediate the internalization of Htt proteins in recipient cells. Together, these results underline the importance of the Cc structure in the process of intercellular propagation of Htt polyQ aggregates and suggest that interfering with Cc formation might be a therapeutic strategy for HD.
Keywords: huntingtin; prion-like propagation; aggregation huntingtin; prion-like propagation; aggregation

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MDPI and ACS Style

Bosica, M.; Grasselli, C.; Panfili, A.; Orsini, F.; Fioriti, L. Coiled-Coil Structures Mediate the Intercellular Propagation of Huntingtin. Int. J. Mol. Sci. 2025, 26, 8162. https://doi.org/10.3390/ijms26178162

AMA Style

Bosica M, Grasselli C, Panfili A, Orsini F, Fioriti L. Coiled-Coil Structures Mediate the Intercellular Propagation of Huntingtin. International Journal of Molecular Sciences. 2025; 26(17):8162. https://doi.org/10.3390/ijms26178162

Chicago/Turabian Style

Bosica, Marco, Chiara Grasselli, Andrea Panfili, Franca Orsini, and Luana Fioriti. 2025. "Coiled-Coil Structures Mediate the Intercellular Propagation of Huntingtin" International Journal of Molecular Sciences 26, no. 17: 8162. https://doi.org/10.3390/ijms26178162

APA Style

Bosica, M., Grasselli, C., Panfili, A., Orsini, F., & Fioriti, L. (2025). Coiled-Coil Structures Mediate the Intercellular Propagation of Huntingtin. International Journal of Molecular Sciences, 26(17), 8162. https://doi.org/10.3390/ijms26178162

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