Conformational change and GTPase activity of human tubulin: A comparative study on Alzheimer's disease and healthy brain.

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 Förster 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.

• Authors: Shima Rajaei, Saeed Karima, Hessam Sepasi Tehrani, Somayeh Shateri, Somayeh Mahmoodi Baram, Meisam Mahdavi, Farzad Mokhtari, Alimohammad Alimohammadi, Abbas Tafakhori, Abolfazl Amiri, Vajiheh Aghamollaii, Hamid Fatemi, Masoumeh Rajabibazl, Farzad Kobarfard, Ali Gorji
• Journal: Journal of neurochemistry (J Neurochem) Vol. 155 Issue 2 Pg. 207-224 (09 2020) ISSN: 1471-4159 [Electronic] England
• PMID: 32196663 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 International Society for Neurochemistry.

Chemical References

• Tubulin
• tau Proteins
• GTP Phosphohydrolases
• Paclitaxel

Topics

• Adult
• Aged
• Aged, 80 and over
• Alzheimer Disease (metabolism)
• Brain Chemistry (genetics)
• Female
• GTP Phosphohydrolases (chemistry, metabolism)
• Humans
• Male
• Microtubules (metabolism)
• Paclitaxel (pharmacology)
• Protein Conformation
• Tubulin (metabolism)
• tau Proteins (metabolism)