Conformational change and GTPase activity of human tubulin: A comparative study on Alzheimer's disease and healthy brain. Issue 2 (13th April 2020)

• Record Type: Journal Article
• Authors: Rajaei, Shima; Karima, Saeed; Sepasi Tehrani, Hessam; Shateri, Somayeh; Mahmoodi Baram, Somayeh; Mahdavi, Meisam; Mokhtari, Farzad; Alimohammadi, Alimohammad; Tafakhori, Abbas; Amiri, Abolfazl; Aghamollaii, Vajiheh; Fatemi, Hamid; Rajabibazl, Masoumeh; Kobarfard, Farzad; Gorji, Ali
• Is Part Of: Journal of neurochemistry. Volume 155:Issue 2(2020)
• Page Start: 207
• Page End: 224
• Publication Date: 2020-04-13
• Subjects: Alzheimer's disease -- dynamic instability -- FRET -- GTPase activity -- microtubules -- tubulin; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15009
• Languages: English
• ISSNs: 0022-3042

Abstract

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. Abstract : Axonal microtubule disintegration and neuronal death are characteristics of Alzheimer's disease. GTP‐cap which is comprised of GTP‐tubulin is highly important in microtubule dynamic instability. We proposed that in Alzheimer's disease age‐dependent conformational changes of tubulin causing altered intrinsic tubulin GTPase activity and decreased GTP‐cap length precedes tau detachment and its subsequent hyperphosphorylation. Human tubulin was purified from normal young adult, normal aged and Alzheimer's brains. Prolonged lag phase, increased critical concentration and GTPase activity concurrent with profound conformational changes and contracted intermolecular MT‐tau distances were found in Alzheimer' brains compared with normal young and aged ones.