FTIR studies of the high pressure dissociation of insulin and alpha-synuclein amyloids

Risultato della ricerca: Other contribution

Abstract

Amyloid fibrils are highly ordered aggregates whose formation occurs during the development of several serious disorders, like Althzeimer's and Parkinson's diseases. Even if most biophysical investigations of fibril formation have attempted to elucidate the structural events that occur during amyloid fibril assembly, relatively little is known about the thermodynamics of the aggregated protein state, and the kinetic mechanisms of its formation. Fibrillation is an irreversible process and a key challenge for the field is the development of therapeutic strategies able to inhibit or reverse the aggregation. The coupling of conventional Fourier Transform Infrared Spectroscopy (FTIR) and high Pressure (HP) techniques has proven to be during the last years a perfect combination for the study of proteins aggregation and misfolding, allowing to explore proteins conformational states not accessible at ambient pressure. In contrast to temperature, whose effect manifests both on volume and thermal energy simultaneously, pressure leads to a controlled change of inter- and intramolecular distances and enables to determine the stability of a protein structure and to stabilize intermediate states that are usually not detectable at ambient pressure or through thermal perturbation. Due to its effect on the energetic of the system, a pressure increase will act on packing defects and empty cavities favouring all that processes that lead to a reduction of the system's volume. We present here the HP-induced disaggregation of two amyloidogenic proteins, insulin and a-synuclein. Insulin aggregation into amyloid-like structures represents a serious problem in its storage as pharmaceutical for the treatment of diabetes mellitus while the interest in studying a- synuclein resides in its involvement in Parkinson's disease. According to our experimental evidences high pressure induces the disaggregation of fibrils with an efficacy that depends on their maturation stage in the case of insulin and on the specific point mutation occurred in protein primary structure in the case of synuclein. Moreover, high pressure dissociation has been found to act in a sequential way, in accordance with the hierarchy of structures.
Lingua originaleEnglish
Stato di pubblicazionePublished - 2012

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alpha-Synuclein
Fourier Transform Infrared Spectroscopy
Amyloid
Insulin
Pressure
Synucleins
Parkinson Disease
Hot Temperature
Amyloidogenic Proteins
Proteins
Protein Stability
Thermodynamics
Point Mutation
Amino Acid Sequence
Diabetes Mellitus
Temperature

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title = "FTIR studies of the high pressure dissociation of insulin and alpha-synuclein amyloids",
abstract = "Amyloid fibrils are highly ordered aggregates whose formation occurs during the development of several serious disorders, like Althzeimer's and Parkinson's diseases. Even if most biophysical investigations of fibril formation have attempted to elucidate the structural events that occur during amyloid fibril assembly, relatively little is known about the thermodynamics of the aggregated protein state, and the kinetic mechanisms of its formation. Fibrillation is an irreversible process and a key challenge for the field is the development of therapeutic strategies able to inhibit or reverse the aggregation. The coupling of conventional Fourier Transform Infrared Spectroscopy (FTIR) and high Pressure (HP) techniques has proven to be during the last years a perfect combination for the study of proteins aggregation and misfolding, allowing to explore proteins conformational states not accessible at ambient pressure. In contrast to temperature, whose effect manifests both on volume and thermal energy simultaneously, pressure leads to a controlled change of inter- and intramolecular distances and enables to determine the stability of a protein structure and to stabilize intermediate states that are usually not detectable at ambient pressure or through thermal perturbation. Due to its effect on the energetic of the system, a pressure increase will act on packing defects and empty cavities favouring all that processes that lead to a reduction of the system's volume. We present here the HP-induced disaggregation of two amyloidogenic proteins, insulin and a-synuclein. Insulin aggregation into amyloid-like structures represents a serious problem in its storage as pharmaceutical for the treatment of diabetes mellitus while the interest in studying a- synuclein resides in its involvement in Parkinson's disease. According to our experimental evidences high pressure induces the disaggregation of fibrils with an efficacy that depends on their maturation stage in the case of insulin and on the specific point mutation occurred in protein primary structure in the case of synuclein. Moreover, high pressure dissociation has been found to act in a sequential way, in accordance with the hierarchy of structures.",
keywords = "amyloids, high pressure, proteins",
author = "Federica Piccirilli",
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AU - Piccirilli, Federica

PY - 2012

Y1 - 2012

N2 - Amyloid fibrils are highly ordered aggregates whose formation occurs during the development of several serious disorders, like Althzeimer's and Parkinson's diseases. Even if most biophysical investigations of fibril formation have attempted to elucidate the structural events that occur during amyloid fibril assembly, relatively little is known about the thermodynamics of the aggregated protein state, and the kinetic mechanisms of its formation. Fibrillation is an irreversible process and a key challenge for the field is the development of therapeutic strategies able to inhibit or reverse the aggregation. The coupling of conventional Fourier Transform Infrared Spectroscopy (FTIR) and high Pressure (HP) techniques has proven to be during the last years a perfect combination for the study of proteins aggregation and misfolding, allowing to explore proteins conformational states not accessible at ambient pressure. In contrast to temperature, whose effect manifests both on volume and thermal energy simultaneously, pressure leads to a controlled change of inter- and intramolecular distances and enables to determine the stability of a protein structure and to stabilize intermediate states that are usually not detectable at ambient pressure or through thermal perturbation. Due to its effect on the energetic of the system, a pressure increase will act on packing defects and empty cavities favouring all that processes that lead to a reduction of the system's volume. We present here the HP-induced disaggregation of two amyloidogenic proteins, insulin and a-synuclein. Insulin aggregation into amyloid-like structures represents a serious problem in its storage as pharmaceutical for the treatment of diabetes mellitus while the interest in studying a- synuclein resides in its involvement in Parkinson's disease. According to our experimental evidences high pressure induces the disaggregation of fibrils with an efficacy that depends on their maturation stage in the case of insulin and on the specific point mutation occurred in protein primary structure in the case of synuclein. Moreover, high pressure dissociation has been found to act in a sequential way, in accordance with the hierarchy of structures.

AB - Amyloid fibrils are highly ordered aggregates whose formation occurs during the development of several serious disorders, like Althzeimer's and Parkinson's diseases. Even if most biophysical investigations of fibril formation have attempted to elucidate the structural events that occur during amyloid fibril assembly, relatively little is known about the thermodynamics of the aggregated protein state, and the kinetic mechanisms of its formation. Fibrillation is an irreversible process and a key challenge for the field is the development of therapeutic strategies able to inhibit or reverse the aggregation. The coupling of conventional Fourier Transform Infrared Spectroscopy (FTIR) and high Pressure (HP) techniques has proven to be during the last years a perfect combination for the study of proteins aggregation and misfolding, allowing to explore proteins conformational states not accessible at ambient pressure. In contrast to temperature, whose effect manifests both on volume and thermal energy simultaneously, pressure leads to a controlled change of inter- and intramolecular distances and enables to determine the stability of a protein structure and to stabilize intermediate states that are usually not detectable at ambient pressure or through thermal perturbation. Due to its effect on the energetic of the system, a pressure increase will act on packing defects and empty cavities favouring all that processes that lead to a reduction of the system's volume. We present here the HP-induced disaggregation of two amyloidogenic proteins, insulin and a-synuclein. Insulin aggregation into amyloid-like structures represents a serious problem in its storage as pharmaceutical for the treatment of diabetes mellitus while the interest in studying a- synuclein resides in its involvement in Parkinson's disease. According to our experimental evidences high pressure induces the disaggregation of fibrils with an efficacy that depends on their maturation stage in the case of insulin and on the specific point mutation occurred in protein primary structure in the case of synuclein. Moreover, high pressure dissociation has been found to act in a sequential way, in accordance with the hierarchy of structures.

KW - amyloids

KW - high pressure

KW - proteins

UR - http://hdl.handle.net/10447/65408

M3 - Other contribution

ER -