Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers
The aggregation of α-synuclein (α-syn) into neurotoxic oligomers and fibrils is an important pathogenic feature of synucleinopatheis, including Parkinson’s disease (PD). A further characteristic of PD is the oxidative stress that results in the formation of aldehydes by lipid peroxidation. It has be...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14630 |
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| author | Nishant Vaikath Indulekha Sudhakaran Ilham Abdi Vijay Gupta Nour Majbour Simona Ghanem Houari Abdesselem Kostas Vekrellis Omar El-Agnaf |
| author_facet | Nishant Vaikath Indulekha Sudhakaran Ilham Abdi Vijay Gupta Nour Majbour Simona Ghanem Houari Abdesselem Kostas Vekrellis Omar El-Agnaf |
| author_sort | Nishant Vaikath |
| collection | DOAJ |
| description | The aggregation of α-synuclein (α-syn) into neurotoxic oligomers and fibrils is an important pathogenic feature of synucleinopatheis, including Parkinson’s disease (PD). A further characteristic of PD is the oxidative stress that results in the formation of aldehydes by lipid peroxidation. It has been reported that the brains of deceased patients with PD contain high levels of protein oligomers that are cross-linked to these aldehydes. Increasing evidence also suggests that prefibrillar oligomeric species are more toxic than the mature amyloid fibrils. However, due to the heterogenous and metastable nature, characterization of the α-syn oligomeric species has been challenging. Here, we generated and characterized distinct α-syn oligomers in vitro in the presence of DA and lipid peroxidation products 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). HNE and ONE oligomer were stable towards the treatment with SDS, urea, and temperature. The secondary structure analysis revealed that only HNE and ONE oligomers contain β-sheet content. In the seeding assay, both DA and ONE oligomers significantly accelerated the aggregation. Furthermore, all oligomeric preparations were found to seed the aggregation of α-syn monomers in vitro and found to be cytotoxic when added to SH-SY5Y cells. Finally, both HNE and ONE α-syn oligomers can be used as a calibrator in an α-syn oligomers-specific ELISA. |
| first_indexed | 2024-03-09T17:46:31Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:31Z |
| publishDate | 2022-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7058cd6e87ef469e97f671f7d6ee9acd2023-11-24T11:05:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231463010.3390/ijms232314630Structural and Biophysical Characterization of Stable Alpha-Synuclein OligomersNishant Vaikath0Indulekha Sudhakaran1Ilham Abdi2Vijay Gupta3Nour Majbour4Simona Ghanem5Houari Abdesselem6Kostas Vekrellis7Omar El-Agnaf8Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarNeurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarNeurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarNeurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarNeurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarNeurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarNeurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarCenter of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, GreeceNeurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha P.O. Box 5825, QatarThe aggregation of α-synuclein (α-syn) into neurotoxic oligomers and fibrils is an important pathogenic feature of synucleinopatheis, including Parkinson’s disease (PD). A further characteristic of PD is the oxidative stress that results in the formation of aldehydes by lipid peroxidation. It has been reported that the brains of deceased patients with PD contain high levels of protein oligomers that are cross-linked to these aldehydes. Increasing evidence also suggests that prefibrillar oligomeric species are more toxic than the mature amyloid fibrils. However, due to the heterogenous and metastable nature, characterization of the α-syn oligomeric species has been challenging. Here, we generated and characterized distinct α-syn oligomers in vitro in the presence of DA and lipid peroxidation products 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). HNE and ONE oligomer were stable towards the treatment with SDS, urea, and temperature. The secondary structure analysis revealed that only HNE and ONE oligomers contain β-sheet content. In the seeding assay, both DA and ONE oligomers significantly accelerated the aggregation. Furthermore, all oligomeric preparations were found to seed the aggregation of α-syn monomers in vitro and found to be cytotoxic when added to SH-SY5Y cells. Finally, both HNE and ONE α-syn oligomers can be used as a calibrator in an α-syn oligomers-specific ELISA.https://www.mdpi.com/1422-0067/23/23/14630alpha-synucleinoligomersHNEONEDAParkinson’s disease |
| spellingShingle | Nishant Vaikath Indulekha Sudhakaran Ilham Abdi Vijay Gupta Nour Majbour Simona Ghanem Houari Abdesselem Kostas Vekrellis Omar El-Agnaf Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers International Journal of Molecular Sciences alpha-synuclein oligomers HNE ONE DA Parkinson’s disease |
| title | Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers |
| title_full | Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers |
| title_fullStr | Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers |
| title_full_unstemmed | Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers |
| title_short | Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers |
| title_sort | structural and biophysical characterization of stable alpha synuclein oligomers |
| topic | alpha-synuclein oligomers HNE ONE DA Parkinson’s disease |
| url | https://www.mdpi.com/1422-0067/23/23/14630 |
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