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Lysine Ε-Aminolysis and Incorporation of Sulfhydryl Groups Into Human Brain Tau 4R/1N and 306Vqivyk311 Enhances the Formation of Beta Structures and Toxicity Publisher Pubmed



Salmani F1 ; Mohammadi M2 ; Seif R2 ; Khatami SH1 ; Noori S1 ; Tehrani HS3 ; Riazi G4 ; Balalaie S5 ; Moosavimovahedi AA4 ; Fard AM6 ; Mahnam K7 ; Keramatinia A8 ; Tafakhori A9 ; Aghamollaii V10 Show All Authors
Authors
  1. Salmani F1
  2. Mohammadi M2
  3. Seif R2
  4. Khatami SH1
  5. Noori S1
  6. Tehrani HS3
  7. Riazi G4
  8. Balalaie S5
  9. Moosavimovahedi AA4
  10. Fard AM6
  11. Mahnam K7
  12. Keramatinia A8
  13. Tafakhori A9
  14. Aghamollaii V10
  15. Toutounchi AH11
  16. Shahmohammadi MR12
  17. Karima S1
Show Affiliations
Authors Affiliations
  1. 1. Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
  2. 2. Student Research Committee, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  3. 3. Clinical Study Department, Behbalin Inc., Tehran, Iran
  4. 4. Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
  5. 5. Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran, Iran
  6. 6. Universal Scientific Education and Research Network (USERN), Tehran, Iran
  7. 7. Faculty of Science, Department of Biology, Nanotechnology Research Center, Sharekord University, Sharekord, Iran
  8. 8. Department of Community Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  9. 9. Department of Neurology, School of Medicine, Iranian Center of Neurological Research, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  10. 10. Neurology Department, Roozbeh Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  11. 11. Department of general surgery, Imam Hosein medical and educational center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  12. 12. Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran

Source: International Journal of Biological Macromolecules Published:2024


Abstract

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. © 2024 Elsevier B.V.