Multiple Roles of Heparin in the Aggregation of p25α

Nielsen, Søren Achim; Yde, Pernille; Giehm, Lise; Sundbye, Sabrina; Christiansen, Gunna; Mathiesen, Joachim; Jensen, Mogens H.; Jensen, Poul Henning; Otzen, Daniel E.

doi:10.1016/j.jmb.2012.01.050

Cited by 22 publications

(25 citation statements)

References 46 publications

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“…3 and 4, top and middle sections), there is enough inducer to allow Tau to bind and nucleate to a significant extent before the second inducer binding step occurs; but at higher inducer concentrations, binding of additional heparin/enoxaparin to the growing "Tau/inducer" complexes occurs so rapidly as to block further incorporation of Tau. The same observations were reported for the brain-specific protein; p25α [44]. As indicated in [6] and [45], the peak of this bell-shaped pattern lies at a ratio of ~3 or ~4.…”

Section: Amyloid Fibril Formation By 1n4r Tau In the Presence Of Hepasupporting

confidence: 81%

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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Section: Amyloid Fibril Formation By 1n4r Tau In the Presence Of Hepasupporting

confidence: 81%

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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“…The formation of the pathological tau filaments has been reported, the development of which are promoted by the presence of MTs19. No TPPP/p25 filament formations have been detected as indicated in a recent paper as well to our knowledge; however, the formation of α-synuclein filaments has been established at substoichiometric TPPP/p25 concentration21.…”

Section: Discussionmentioning

confidence: 70%

Further evidence for microtubule-independent dimerization of TPPP/p25

Oláh

Szénási

Szunyogh

et al. 2017

Sci Rep

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Tubulin Polymerization Promoting Protein (TPPP/p25) is a brain-specific disordered protein that modulates the dynamics and stability of the microtubule network by its assembly promoting, cross-linking and acetylation enhancing activities. In normal brain it is expressed primarily in differentiated oligodendrocytes; however, at pathological conditions it is enriched in inclusions of both neurons and oligodendrocytes characteristic for Parkinson’s disease and multiple system atrophy, respectively. The objective of this paper is to highlight a critical point of a recently published Skoufias’s paper in which the crucial role of the microtubules in TPPP/p25 dimerization leading to microtubule bundling was suggested. However, our previous and present data provide evidence for the microtubule-independent dimerization of TPPP/p25 and its stabilization by disulphide bridges. In addition, our bimolecular fluorescence complementation experiments revealed the dimerization ability of both the full length and the terminal-free (CORE) TPPP/p25 forms, however, while TPPP/p25 aligned along the bundled microtubule network, the associated CORE segments distributed mostly homogeneously within the cytosol. Now, we identified a molecular model from the possible ones suggested in the Skoufias’s paper that could be responsible for stabilization of the microtubule network in the course of the oligodendrocyte differentiation, consequently in the constitution of the myelin sheath.

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“…A slight increase in the ThT fluorescence is observed for HsTPI n after 40 hours. Nevertheless this low fluorescence intensity was not indicative of βaggregation; the more drastic increment in turbidity, as indicated by the dispersion of visible light, suggests that it is more likely an interference of non-specific binding of the ThT to disordered aggregates, as displayed by other amorphous assemblies (Biancalana & Koide, 2010;Nielsen et al, 2012;Scarafone et al, 2012). HsTPI urea , on the other hand, displayed a fast but small increase in turbidity ( Figure 1B), while ThT fluorescence showed a more significant increase ( Figure 1A).…”

Section: Resultsmentioning

confidence: 95%

Peer Review #1 of "Identification of fibrillogenic regions in human triosephosphate isomerase (v0.1)"

2016

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Multiple Roles of Heparin in the Aggregation of p25α

Cited by 22 publications

References 46 publications

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

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

Further evidence for microtubule-independent dimerization of TPPP/p25

Peer Review #1 of "Identification of fibrillogenic regions in human triosephosphate isomerase (v0.1)"

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