Wildtype and A30P mutant alpha-synuclein form different fibril structures.
Parkinson's Disease (PD) is a neurodegenerative movement disorder affecting millions of people worldwide. One of the key players in the development of the disease is the protein α-synuclein (aSN), which aggregates in the brain of PD patients. The aSN mutant A30P has been reported to cause early...
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/40586476b9e64459bf62751891354a2b |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:40586476b9e64459bf62751891354a2b |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:40586476b9e64459bf62751891354a2b2021-11-18T07:38:36ZWildtype and A30P mutant alpha-synuclein form different fibril structures.1932-620310.1371/journal.pone.0067713https://doaj.org/article/40586476b9e64459bf62751891354a2b2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23861789/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Parkinson's Disease (PD) is a neurodegenerative movement disorder affecting millions of people worldwide. One of the key players in the development of the disease is the protein α-synuclein (aSN), which aggregates in the brain of PD patients. The aSN mutant A30P has been reported to cause early-onset familial PD and shows different aggregation behavior compared to wt aSN. Here we use a multidisciplinary approach to compare the aggregation process of wt and A30P aSN. In agreement with previous studies, we observe an initial lag phase followed by a continuous structural development of fibrils until reaching an apparent monomer-aggregate equilibrium state and a plateau in Thioflavin T (ThT) fluorescence intensity. However, at later timepoints A30P shows greater propensity than αSN wt to form dense bundled fibril networks. Combining small angle x-ray scattering, x-ray fibre diffraction and linear dichroism, we demonstrate that while the microscopic structure of the individual fibril essentially remains constant throughout the experiment, the formation of dense A30P fibril networks occur through a continuous assembly pathway while the formation of less dense wt fibril networks with fewer contact points follows a continuous path during the elongation phase and a second rearrangement phase after reaching the ThT fluorescence plateau. Our work thus highlights that structural rearrangements proceed beyond the plateau in ThT-based monitoring of the fibrillation process, and the density and morphology of the resulting fibril networks is highly dependent on the aSN form studied.Søren Bang NielsenFrancesca MacchiSamuele RaccostaAnnette Eva LangkildeLise GiehmAnders KyrstingAnna Sigrid Pii SvaneMauro MannoGunna ChristiansenNiels Christian NielsenLene OddershedeBente VestergaardDaniel Erik OtzenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e67713 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Søren Bang Nielsen Francesca Macchi Samuele Raccosta Annette Eva Langkilde Lise Giehm Anders Kyrsting Anna Sigrid Pii Svane Mauro Manno Gunna Christiansen Niels Christian Nielsen Lene Oddershede Bente Vestergaard Daniel Erik Otzen Wildtype and A30P mutant alpha-synuclein form different fibril structures. |
| description |
Parkinson's Disease (PD) is a neurodegenerative movement disorder affecting millions of people worldwide. One of the key players in the development of the disease is the protein α-synuclein (aSN), which aggregates in the brain of PD patients. The aSN mutant A30P has been reported to cause early-onset familial PD and shows different aggregation behavior compared to wt aSN. Here we use a multidisciplinary approach to compare the aggregation process of wt and A30P aSN. In agreement with previous studies, we observe an initial lag phase followed by a continuous structural development of fibrils until reaching an apparent monomer-aggregate equilibrium state and a plateau in Thioflavin T (ThT) fluorescence intensity. However, at later timepoints A30P shows greater propensity than αSN wt to form dense bundled fibril networks. Combining small angle x-ray scattering, x-ray fibre diffraction and linear dichroism, we demonstrate that while the microscopic structure of the individual fibril essentially remains constant throughout the experiment, the formation of dense A30P fibril networks occur through a continuous assembly pathway while the formation of less dense wt fibril networks with fewer contact points follows a continuous path during the elongation phase and a second rearrangement phase after reaching the ThT fluorescence plateau. Our work thus highlights that structural rearrangements proceed beyond the plateau in ThT-based monitoring of the fibrillation process, and the density and morphology of the resulting fibril networks is highly dependent on the aSN form studied. |
| format |
article |
| author |
Søren Bang Nielsen Francesca Macchi Samuele Raccosta Annette Eva Langkilde Lise Giehm Anders Kyrsting Anna Sigrid Pii Svane Mauro Manno Gunna Christiansen Niels Christian Nielsen Lene Oddershede Bente Vestergaard Daniel Erik Otzen |
| author_facet |
Søren Bang Nielsen Francesca Macchi Samuele Raccosta Annette Eva Langkilde Lise Giehm Anders Kyrsting Anna Sigrid Pii Svane Mauro Manno Gunna Christiansen Niels Christian Nielsen Lene Oddershede Bente Vestergaard Daniel Erik Otzen |
| author_sort |
Søren Bang Nielsen |
| title |
Wildtype and A30P mutant alpha-synuclein form different fibril structures. |
| title_short |
Wildtype and A30P mutant alpha-synuclein form different fibril structures. |
| title_full |
Wildtype and A30P mutant alpha-synuclein form different fibril structures. |
| title_fullStr |
Wildtype and A30P mutant alpha-synuclein form different fibril structures. |
| title_full_unstemmed |
Wildtype and A30P mutant alpha-synuclein form different fibril structures. |
| title_sort |
wildtype and a30p mutant alpha-synuclein form different fibril structures. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/40586476b9e64459bf62751891354a2b |
| work_keys_str_mv |
AT sørenbangnielsen wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT francescamacchi wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT samueleraccosta wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT annetteevalangkilde wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT lisegiehm wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT anderskyrsting wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT annasigridpiisvane wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT mauromanno wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT gunnachristiansen wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT nielschristiannielsen wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT leneoddershede wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT bentevestergaard wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures AT danielerikotzen wildtypeanda30pmutantalphasynucleinformdifferentfibrilstructures |
| _version_ |
1718423154355863552 |