Lysine ε-aminolysis and incorporation of sulfhydryl groups into human brain tau 4R/1N and 306VQIVYK311 enhances the formation of beta structures and toxicity
Copyright © 2024 Elsevier B.V. All rights reserved..
In the present study, we investigated the effects of N-homocysteine thiolactone (tHcy) modification on expressed and purified tau protein and the synthesized VQIVYK target peptide. The modified constructs were subjected to comprehensive validation using various methodologies, including mass spectrometry. Subsequently, in vivo, in vitro, and in silico characterizations were performed under both reducing and non-reducing conditions, as well as in the presence and absence of heparin as a cofactor. Our results unequivocally confirmed that under reducing conditions and in the presence of heparin, the modified constructs exhibited a greater propensity for aggregation. This enhanced aggregative behavior can be attributed to the disruption of lysine positive charges and the subsequent influence of hydrophobic and p-stacking intermolecular forces. Notably, the modified oligomeric species induced apoptosis in the SH-SY5Y cell line, and this effect was further exacerbated with longer incubation times and higher concentrations of the modifier. These observations suggest a potential mechanism involving reactive oxygen species (ROS). To gain a deeper understanding of the molecular mechanisms underlying the neurotoxic effects, further investigations are warranted. Elucidating these mechanisms will contribute to the development of more effective strategies to counteract aggregation and mitigate neurodegeneration.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:263 |
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| Enthalten in: |
International journal of biological macromolecules - 263(2024), Pt 1 vom: 01. März, Seite 130223 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Salmani, Farzaneh [VerfasserIn] |
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| Links: |
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| Themen: |
9005-49-6 |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ijbiomac.2024.130223 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 245 | 1 | 0 | |a Lysine ε-aminolysis and incorporation of sulfhydryl groups into human brain tau 4R/1N and 306VQIVYK311 enhances the formation of beta structures and toxicity |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier B.V. All rights reserved. | ||
| 520 | |a In the present study, we investigated the effects of N-homocysteine thiolactone (tHcy) modification on expressed and purified tau protein and the synthesized VQIVYK target peptide. The modified constructs were subjected to comprehensive validation using various methodologies, including mass spectrometry. Subsequently, in vivo, in vitro, and in silico characterizations were performed under both reducing and non-reducing conditions, as well as in the presence and absence of heparin as a cofactor. Our results unequivocally confirmed that under reducing conditions and in the presence of heparin, the modified constructs exhibited a greater propensity for aggregation. This enhanced aggregative behavior can be attributed to the disruption of lysine positive charges and the subsequent influence of hydrophobic and p-stacking intermolecular forces. Notably, the modified oligomeric species induced apoptosis in the SH-SY5Y cell line, and this effect was further exacerbated with longer incubation times and higher concentrations of the modifier. These observations suggest a potential mechanism involving reactive oxygen species (ROS). To gain a deeper understanding of the molecular mechanisms underlying the neurotoxic effects, further investigations are warranted. Elucidating these mechanisms will contribute to the development of more effective strategies to counteract aggregation and mitigate neurodegeneration | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Aggregation | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a Intermolecular forces | |
| 650 | 4 | |a N-homocysteinylation | |
| 650 | 4 | |a Neurodegeneration | |
| 650 | 4 | |a Tau | |
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| 700 | 1 | |a Mohammadi, Marjan |e verfasserin |4 aut | |
| 700 | 1 | |a Seif, Roozbeh |e verfasserin |4 aut | |
| 700 | 1 | |a Khatami, Seyyed Hossein |e verfasserin |4 aut | |
| 700 | 1 | |a Noori, Shokoofeh |e verfasserin |4 aut | |
| 700 | 1 | |a Tehrani, Hessam Sepasi |e verfasserin |4 aut | |
| 700 | 1 | |a Riazi, Gholamhossein |e verfasserin |4 aut | |
| 700 | 1 | |a Balalaie, Saeed |e verfasserin |4 aut | |
| 700 | 1 | |a Moosavi-Movahedi, Ali Akbar |e verfasserin |4 aut | |
| 700 | 1 | |a Fard, Atousa Moghadam |e verfasserin |4 aut | |
| 700 | 1 | |a Mahnam, Karim |e verfasserin |4 aut | |
| 700 | 1 | |a Keramatinia, Aliasghar |e verfasserin |4 aut | |
| 700 | 1 | |a Tafakhori, Abbas |e verfasserin |4 aut | |
| 700 | 1 | |a Aghamollaii, Vajiheh |e verfasserin |4 aut | |
| 700 | 1 | |a Toutounchi, Alireza Haghbin |e verfasserin |4 aut | |
| 700 | 1 | |a Shahmohammadi, Mohammad Reza |e verfasserin |4 aut | |
| 700 | 1 | |a Karima, Saeed |e verfasserin |4 aut | |
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