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Conformational Change and Gtpase Activity of Human Tubulin: A Comparative Study on Alzheimer’S Disease and Healthy Brain Publisher Pubmed



Rajaei S1 ; Karima S1 ; Sepasi Tehrani H2 ; Shateri S1 ; Mahmoodi Baram S1, 2 ; Mahdavi M1 ; Mokhtari F2, 5 ; Alimohammadi A3 ; Tafakhori A4 ; Amiri A3 ; Aghamollaii V6 ; Fatemi H2 ; Rajabibazl M1 ; Kobarfard F7 Show All Authors
Authors
  1. Rajaei S1
  2. Karima S1
  3. Sepasi Tehrani H2
  4. Shateri S1
  5. Mahmoodi Baram S1, 2
  6. Mahdavi M1
  7. Mokhtari F2, 5
  8. Alimohammadi A3
  9. Tafakhori A4
  10. Amiri A3
  11. Aghamollaii V6
  12. Fatemi H2
  13. Rajabibazl M1
  14. Kobarfard F7
  15. Gorji A8
Show Affiliations
Authors Affiliations
  1. 1. Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
  2. 2. HealthWeX Clinical Research Co., Ltd., Toronto, ON, Canada
  3. 3. Research Center of Tehran Forensic Medicine Organization, Forensic Medicine, Legal Medicine Organization Research Center, Tehran, Iran
  4. 4. Iranian Center of Neurological research, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
  6. 6. Neurology Department, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
  7. 7. Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
  8. 8. Department of Neurology and Department of Neurosurgery, Westfalische Wilhelms-Universitat Munster, Munster, Germany

Source: Journal of Neurochemistry Published:2020


Abstract

In Alzheimer's disease (AD), the most common form of dementia, microtubules (MTs) play a pivotal role through their highly dynamic structure and instability. They mediate axonal transport that is crucial to synaptic viability. MT assembly, dynamic instability and stabilization are modulated by tau proteins, whose detachment initiates MT disintegration. Albeit extensive research, the role of GTPase activity in molecular mechanism of stability remains controversial. We hypothesized that GTPase activity is altered in AD leading to microtubule dynamic dysfunction and ultimately to neuronal death. In this paper, fresh tubulin was purified by chromatography from normal young adult, normal aged, and Alzheimer's brain tissues. Polymerization pattern, assembly kinetics and dynamics, critical concentration, GTPase activity, interaction with tau, intermolecular geometry, and conformational changes were explored via Forster Resonance Energy Transfer (FRET) and various spectroscopy methods. Results showed slower MT assembly process in samples from the brains of people with AD compared with normal young and aged brains. This observation was characterized by prolonged lag phase and increased critical and inactive concentration of tubulin. In addition, the GTPase activity in samples from AD brains was significantly higher than in both normal young and normal aged samples, concurrent with profound conformational changes and contracted intermolecular MT-tau distances as revealed by FRET. These alterations were partially restored in the presence of a microtubule stabilizer, paclitaxel. We proposed that alterations of both tubulin function and GTPase activity may be involved in the molecular neuropathogenesis of AD, thus providing new avenues for therapeutic approaches. (Figure presented.). © 2020 International Society for Neurochemistry
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