Altered tubulin assembly dynamics with <i>N</i>‐homocysteinylated human 4R/1N tau in vitro

Karima, Saeed; Riazi, Gholamhossein; Khodadadi, Sirus; Aryapour, Hassan; Khalili, Mohammad Ali Nasiri; Yousefi, Leila; Moosavi-Movahedi, Ali Akbar

doi:10.1016/j.febslet.2012.09.024

Cited by 20 publications

(14 citation statements)

References 35 publications

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“…Homocysteinlylation of MAPs resulted from the irreversible N-homocysteinylation of lysine residues rather than from the reversible S-homocysteinylation of cysteine residues. Our data are consistent with N-homocysteinylation reported in vitro [22,36,37]. Silencing MARS expression using siRNA prevented homocysteinylation of tau and MAP1a in our cell model, while treatment with mercaptoethanol did not remove homocysteinyl residues, indicating that disulfide bonds were not involved in the homocysteinylation process [24].…”

Section: Discussionsupporting

confidence: 91%

N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Bossenmeyer‐Pourié

Smith

Lehmann

et al. 2019

The Journal of Pathology

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The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule‐associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19‐7 neuroprogenitors lacking folate. Compared with controls, N‐homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N‐homocysteinylation dissociated tau and MAPs from β‐tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β‐tubulin. N‐homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days‐old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy–thiolactone, the substrate of N‐homocysteinylation. Experimental inactivation of MARS prevented the N‐homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β‐tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N‐homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 91%

N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Bossenmeyer‐Pourié

Smith

Lehmann

et al. 2019

The Journal of Pathology

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“…Thus, N-Hcy-tau fails to decrease tubulin dissociation, and the extent of tubulin assembly is reduced as the extent of tau N-homocysteinylation increases [353]. Tau increases the rate of MTP elongation by decreasing tubulin dissociation during assembly.…”

Section: N-hcy-taumentioning

confidence: 98%

“…Interactions of N-Hcy-tau containing 1.6, 7.2, and 25.2 mol N-Hcy/mol protein with MTP and tubulin were studied by ultracentrifugation and SDS-PAGE analyses [353]. After ultracentrifugation of mixtures containing MTP and N-Hcy-tau or control unmodified tau, N-Hcy-tau is found predominantly in the supernatant, while control tau is found in the pellet.…”

Section: N-hcy-taumentioning

confidence: 99%

Homocysteine in Protein Structure/Function and Human Disease

Jakubowski¹

2013

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“…It has been found that these isoforms stabilize MTP both in vitro and in vivo and 4R Tau stabilizes MTP more strongly and also overexpresses in AD condition compared to 3R isoform [11]. In this way, the positive lysine residues in the MTBRs of Tau interact with the negative C-terminal of tubulin in a sequence-specific fashion [12].…”

Section: Introductionmentioning

confidence: 97%

Appraisal of role of the polyanionic inducer length on amyloid formation by 412-residue 1N4R Tau protein: A comparative study

Jangholi

Ashrafi-Kooshk

Arab

et al. 2016

Archives of Biochemistry and Biophysics

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In many neurodegenerative diseases, formation of protein fibrillar aggregates has been observed as a major pathological change. Neurofibrillary tangles, mainly composed of fibrils formed by the microtubule-associated protein; Tau, are a hallmark of a group of neurodegenerative diseases such as Alzheimer's disease. Tau belongs to the class of natively unfolded proteins and partially folds into an ordered β-structure during aggregation. Polyanionic cofactors such as heparin are commonly used as inducer of Tau aggregation in vitro. The role of heparin in nucleation and elongation steps during Tau fibril formation is not fully understood. In the current study, aggregation kinetics as well as structure of Tau amyloid fibrils, by using the 1N4R isoform, have been reproducibly determined in the presence of heparin and the shorter molecule; enoxaparin. The kinetic studies demonstrated that heparin (not enoxaparin) efficiently accelerates Tau amyloid formation and revealed, mechanistically, that the molecular weight of the inducer is important in accelerating amyloidogenesis. The kinetic parameter values of Tau amyloid aggregation, especially, the amyloid aggregation extent, were relatively different in the presence of heparin and enoxaparin, at various stoichiometries of the inducers binding. Also, based on the results, obtained from CD, FTIR, AFM and XRD studies, it may be suggested that the inducer length plays a critical role mainly in the nucleation process, so that it determines that oligomers lie on or off the pathway of Tau fibrillization. The biochemical results herein suggest that the chemical environment of the extracellular matrix as well as localization of distinct glycosaminoglycans may influence deposition behavior of Tau amyloidosis.

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Altered tubulin assembly dynamics with N‐homocysteinylated human 4R/1N tau in vitro

Cited by 20 publications

References 35 publications

N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Homocysteine in Protein Structure/Function and Human Disease

Appraisal of role of the polyanionic inducer length on amyloid formation by 412-residue 1N4R Tau protein: A comparative study

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