High-Pressure-Driven Reversible Dissociation of α-Synuclein Fibrils Reveals Structural Hierarchy

Valeria Militello, Federica Piccirilli, Isabella Tessari, Andrea Perucchi, Luigi Bubacco, Mariano Beltramini, Francesco Spinozzi, Marco Brucale, Maria Grazia Ortore, Stefano Lupi, Paolo Mariani, Federica Piccirilli, Nicoletta Plotegher

Risultato della ricerca: Article

6 Citazioni (Scopus)

Abstract

The analysis of the α-synuclein (aS) aggregation process, which is involved in Parkinson's disease etiopathogenesis, and of the structural feature of the resulting amyloid fibrils may shed light on the relationship between the structure of aS aggregates and their toxicity. This may be considered a paradigm of the ground work needed to tackle the molecular basis of all the protein-aggregation-related diseases. With this aim, we used chemical and physical dissociation methods to explore the structural organization of wild-type aS fibrils. High pressure (in the kbar range) and alkaline pH were used to disassemble fibrils to collect information on the hierarchic pathway by which distinct β-sheets sequentially unfold using the unique possibility offered by high-pressure Fourier transform infrared spectroscopy. The results point toward the formation of kinetic traps in the energy landscape of aS fibril disassembly and the presence of transient partially folded species during the process. Since we found that the dissociation of wild-type aS fibrils by high pressure is reversible upon pressure release, the disassembled molecules likely retain structural information that favors fibril reformation. To deconstruct the role of the different regions of aS sequence in this process, we measured the high-pressure dissociation of amyloids formed by covalent chimeric dimers of aS (syn-syn) and by the aS deletion mutant that lacks the C-terminus, i.e., aS (1–99). The results allowed us to single out the role of dimerization and that of the C-terminus in the complete maturation of fibrillar aS.
Lingua originaleEnglish
pagine (da-a)1685-1696
Numero di pagine12
RivistaBiophysical Journal
Volume113
Stato di pubblicazionePublished - 2017

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Synucleins
Pressure
Amyloid
Dimerization
Fourier Transform Infrared Spectroscopy
Parkinson Disease
Proteins

All Science Journal Classification (ASJC) codes

  • Biophysics

Cita questo

Militello, V., Piccirilli, F., Tessari, I., Perucchi, A., Bubacco, L., Beltramini, M., ... Plotegher, N. (2017). High-Pressure-Driven Reversible Dissociation of α-Synuclein Fibrils Reveals Structural Hierarchy. Biophysical Journal, 113, 1685-1696.

High-Pressure-Driven Reversible Dissociation of α-Synuclein Fibrils Reveals Structural Hierarchy. / Militello, Valeria; Piccirilli, Federica; Tessari, Isabella; Perucchi, Andrea; Bubacco, Luigi; Beltramini, Mariano; Spinozzi, Francesco; Brucale, Marco; Ortore, Maria Grazia; Lupi, Stefano; Mariani, Paolo; Piccirilli, Federica; Plotegher, Nicoletta.

In: Biophysical Journal, Vol. 113, 2017, pag. 1685-1696.

Risultato della ricerca: Article

Militello, V, Piccirilli, F, Tessari, I, Perucchi, A, Bubacco, L, Beltramini, M, Spinozzi, F, Brucale, M, Ortore, MG, Lupi, S, Mariani, P, Piccirilli, F & Plotegher, N 2017, 'High-Pressure-Driven Reversible Dissociation of α-Synuclein Fibrils Reveals Structural Hierarchy', Biophysical Journal, vol. 113, pagg. 1685-1696.
Militello, Valeria ; Piccirilli, Federica ; Tessari, Isabella ; Perucchi, Andrea ; Bubacco, Luigi ; Beltramini, Mariano ; Spinozzi, Francesco ; Brucale, Marco ; Ortore, Maria Grazia ; Lupi, Stefano ; Mariani, Paolo ; Piccirilli, Federica ; Plotegher, Nicoletta. / High-Pressure-Driven Reversible Dissociation of α-Synuclein Fibrils Reveals Structural Hierarchy. In: Biophysical Journal. 2017 ; Vol. 113. pagg. 1685-1696.
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abstract = "The analysis of the {\^I}±-synuclein (aS) aggregation process, which is involved in Parkinson's disease etiopathogenesis, and of the structural feature of the resulting amyloid fibrils may shed light on the relationship between the structure of aS aggregates and their toxicity. This may be considered a paradigm of the ground work needed to tackle the molecular basis of all the protein-aggregation-related diseases. With this aim, we used chemical and physical dissociation methods to explore the structural organization of wild-type aS fibrils. High pressure (in the kbar range) and alkaline pH were used to disassemble fibrils to collect information on the hierarchic pathway by which distinct {\^I}²-sheets sequentially unfold using the unique possibility offered by high-pressure Fourier transform infrared spectroscopy. The results point toward the formation of kinetic traps in the energy landscape of aS fibril disassembly and the presence of transient partially folded species during the process. Since we found that the dissociation of wild-type aS fibrils by high pressure is reversible upon pressure release, the disassembled molecules likely retain structural information that favors fibril reformation. To deconstruct the role of the different regions of aS sequence in this process, we measured the high-pressure dissociation of amyloids formed by covalent chimeric dimers of aS (syn-syn) and by the aS deletion mutant that lacks the C-terminus, i.e., aS (1{\^a}€“99). The results allowed us to single out the role of dimerization and that of the C-terminus in the complete maturation of fibrillar aS.",
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AU - Militello, Valeria

AU - Piccirilli, Federica

AU - Tessari, Isabella

AU - Perucchi, Andrea

AU - Bubacco, Luigi

AU - Beltramini, Mariano

AU - Spinozzi, Francesco

AU - Brucale, Marco

AU - Ortore, Maria Grazia

AU - Lupi, Stefano

AU - Mariani, Paolo

AU - Piccirilli, Federica

AU - Plotegher, Nicoletta

PY - 2017

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N2 - The analysis of the α-synuclein (aS) aggregation process, which is involved in Parkinson's disease etiopathogenesis, and of the structural feature of the resulting amyloid fibrils may shed light on the relationship between the structure of aS aggregates and their toxicity. This may be considered a paradigm of the ground work needed to tackle the molecular basis of all the protein-aggregation-related diseases. With this aim, we used chemical and physical dissociation methods to explore the structural organization of wild-type aS fibrils. High pressure (in the kbar range) and alkaline pH were used to disassemble fibrils to collect information on the hierarchic pathway by which distinct β-sheets sequentially unfold using the unique possibility offered by high-pressure Fourier transform infrared spectroscopy. The results point toward the formation of kinetic traps in the energy landscape of aS fibril disassembly and the presence of transient partially folded species during the process. Since we found that the dissociation of wild-type aS fibrils by high pressure is reversible upon pressure release, the disassembled molecules likely retain structural information that favors fibril reformation. To deconstruct the role of the different regions of aS sequence in this process, we measured the high-pressure dissociation of amyloids formed by covalent chimeric dimers of aS (syn-syn) and by the aS deletion mutant that lacks the C-terminus, i.e., aS (1–99). The results allowed us to single out the role of dimerization and that of the C-terminus in the complete maturation of fibrillar aS.

AB - The analysis of the α-synuclein (aS) aggregation process, which is involved in Parkinson's disease etiopathogenesis, and of the structural feature of the resulting amyloid fibrils may shed light on the relationship between the structure of aS aggregates and their toxicity. This may be considered a paradigm of the ground work needed to tackle the molecular basis of all the protein-aggregation-related diseases. With this aim, we used chemical and physical dissociation methods to explore the structural organization of wild-type aS fibrils. High pressure (in the kbar range) and alkaline pH were used to disassemble fibrils to collect information on the hierarchic pathway by which distinct β-sheets sequentially unfold using the unique possibility offered by high-pressure Fourier transform infrared spectroscopy. The results point toward the formation of kinetic traps in the energy landscape of aS fibril disassembly and the presence of transient partially folded species during the process. Since we found that the dissociation of wild-type aS fibrils by high pressure is reversible upon pressure release, the disassembled molecules likely retain structural information that favors fibril reformation. To deconstruct the role of the different regions of aS sequence in this process, we measured the high-pressure dissociation of amyloids formed by covalent chimeric dimers of aS (syn-syn) and by the aS deletion mutant that lacks the C-terminus, i.e., aS (1–99). The results allowed us to single out the role of dimerization and that of the C-terminus in the complete maturation of fibrillar aS.

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