Conformational change and GTPase activity of human tubulin: A comparative study on Alzheimer's disease and healthy brain.
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.
['Rajaei|Shima|S|', 'Karima|Saeed|S|0000-0002-8233-4551', 'Sepasi Tehrani|Hessam|H|', 'Shateri|Somayeh|S|', 'Mahmoodi Baram|Somayeh|S|', 'Mahdavi|Meisam|M|', 'Mokhtari|Farzad|F|', 'Alimohammadi|Alimohammad|A|', 'Tafakhori|Abbas|A|', 'Amiri|Abolfazl|A|', 'Aghamollaii|Vajiheh|V|', 'Fatemi|Hamid|H|', 'Rajabibazl|Masoumeh|M|', 'Kobarfard|Farzad|F|', 'Gorji|Ali|A|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D000544:Alzheimer Disease D001923:Brain Chemistry D005260:Female D020558:GTP Phosphohydrolases D006801:Humans D008297:Male D008870:Microtubules D017239:Paclitaxel D011487:Protein Conformation D014404:Tubulin D016875:tau Proteins
GTPase activity tubulin Alzheimer's disease microtubules dynamic instability FRET