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Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins

There is still no successful strategy to treat Huntington’s disease, an inherited autosomal disorder associated with the aggregation of mutated forms of the huntingtin protein containing polyglutamine tracts with more than 36 repeats. Recent experimental evidence is challenging the conventional view...

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Autores principales: Bonfanti, Silvia, Lionetti, Maria Chiara, Fumagalli, Maria Rita, Chirasani, Venkat R., Tiana, Guido, Dokholyan, Nikolay V., Zapperi, Stefano, La Porta, Caterina A. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527588/
https://www.ncbi.nlm.nih.gov/pubmed/31110208
http://dx.doi.org/10.1038/s41598-019-44151-0
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author Bonfanti, Silvia
Lionetti, Maria Chiara
Fumagalli, Maria Rita
Chirasani, Venkat R.
Tiana, Guido
Dokholyan, Nikolay V.
Zapperi, Stefano
La Porta, Caterina A. M.
author_facet Bonfanti, Silvia
Lionetti, Maria Chiara
Fumagalli, Maria Rita
Chirasani, Venkat R.
Tiana, Guido
Dokholyan, Nikolay V.
Zapperi, Stefano
La Porta, Caterina A. M.
author_sort Bonfanti, Silvia
collection PubMed
description There is still no successful strategy to treat Huntington’s disease, an inherited autosomal disorder associated with the aggregation of mutated forms of the huntingtin protein containing polyglutamine tracts with more than 36 repeats. Recent experimental evidence is challenging the conventional view of the disease by revealing transcellular transfer of mutated huntingtin proteins which are able to seed oligomers involving wild type forms of the protein. Here we decipher the molecular mechanism of this unconventional heterogeneous oligomerization by performing discrete molecular dynamics simulations. We identify the most probable oligomer conformations and the molecular regions that can be targeted to destabilize them. Our computational findings are complemented experimentally by fluorescence-lifetime imaging microscopy/fluorescence resonance energy transfer (FLIM-FRET) of cells co-transfected with huntingtin proteins containing short and large polyglutamine tracts. Our work clarifies the structural features responsible for heterogeneous huntingtin aggregation with possible implications to contrast the prion-like spreading of Huntington’s disease.
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spelling pubmed-65275882019-05-30 Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins Bonfanti, Silvia Lionetti, Maria Chiara Fumagalli, Maria Rita Chirasani, Venkat R. Tiana, Guido Dokholyan, Nikolay V. Zapperi, Stefano La Porta, Caterina A. M. Sci Rep Article There is still no successful strategy to treat Huntington’s disease, an inherited autosomal disorder associated with the aggregation of mutated forms of the huntingtin protein containing polyglutamine tracts with more than 36 repeats. Recent experimental evidence is challenging the conventional view of the disease by revealing transcellular transfer of mutated huntingtin proteins which are able to seed oligomers involving wild type forms of the protein. Here we decipher the molecular mechanism of this unconventional heterogeneous oligomerization by performing discrete molecular dynamics simulations. We identify the most probable oligomer conformations and the molecular regions that can be targeted to destabilize them. Our computational findings are complemented experimentally by fluorescence-lifetime imaging microscopy/fluorescence resonance energy transfer (FLIM-FRET) of cells co-transfected with huntingtin proteins containing short and large polyglutamine tracts. Our work clarifies the structural features responsible for heterogeneous huntingtin aggregation with possible implications to contrast the prion-like spreading of Huntington’s disease. Nature Publishing Group UK 2019-05-20 /pmc/articles/PMC6527588/ /pubmed/31110208 http://dx.doi.org/10.1038/s41598-019-44151-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bonfanti, Silvia
Lionetti, Maria Chiara
Fumagalli, Maria Rita
Chirasani, Venkat R.
Tiana, Guido
Dokholyan, Nikolay V.
Zapperi, Stefano
La Porta, Caterina A. M.
Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
title Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
title_full Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
title_fullStr Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
title_full_unstemmed Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
title_short Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
title_sort molecular mechanisms of heterogeneous oligomerization of huntingtin proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527588/
https://www.ncbi.nlm.nih.gov/pubmed/31110208
http://dx.doi.org/10.1038/s41598-019-44151-0
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