Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins

Silvia Bonfanti, Maria Chiara Lionetti, Maria Rita Fumagalli, Venkat R. Chirasani, Guido Tiana, Nikolay V. Dokholyan, Stefano Zapperi, Caterina A.M. La Porta

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number7615
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Huntington Disease
Molecular Conformation
Fluorescence Resonance Energy Transfer
Prions
Optical Imaging
Molecular Dynamics Simulation
Microscopy
Seeds
Huntingtin Protein
Proteins
polyglutamine

All Science Journal Classification (ASJC) codes

  • General

Cite this

Bonfanti, S., Lionetti, M. C., Fumagalli, M. R., Chirasani, V. R., Tiana, G., Dokholyan, N. V., ... La Porta, C. A. M. (2019). Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins. Scientific reports, 9(1), [7615]. https://doi.org/10.1038/s41598-019-44151-0
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. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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Bonfanti, S, Lionetti, MC, Fumagalli, MR, Chirasani, VR, Tiana, G, Dokholyan, NV, Zapperi, S & La Porta, CAM 2019, 'Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins', Scientific reports, vol. 9, no. 1, 7615. https://doi.org/10.1038/s41598-019-44151-0

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.

In: Scientific reports, Vol. 9, No. 1, 7615, 01.12.2019.

Research output: Contribution to journalArticle

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