ORCID Profile
0000-0002-5214-540X
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Publisher: MDPI AG
Date: 25-04-2022
DOI: 10.3390/BIOM12050630
Abstract: The ision of amyloid fibril particles through fragmentation is implicated in the progression of human neurodegenerative disorders such as Parkinson’s disease. Fragmentation of amyloid fibrils plays a crucial role in the propagation of the amyloid state encoded in their three-dimensional structures and may have an important role in the spreading of potentially pathological properties and phenotypes in amyloid-associated diseases. However, despite the mechanistic importance of fibril fragmentation, the relative stabilities of different types or different polymorphs of amyloid fibrils toward fragmentation remain to be quantified. We have previously developed an approach to compare the relative stabilities of different types of amyloid fibrils toward fragmentation. In this study, we show that controlled sonication, a widely used method of mechanical perturbation for amyloid seed generation, can be used as a form of mechanical perturbation for rapid comparative assessment of the relative fragmentation stabilities of different amyloid fibril structures. This approach is applied to assess the relative fragmentation stabilities of amyloid formed in vitro from wild type (WT) α-synuclein and two familial mutant variants of α-synuclein (A30P and A53T) that generate morphologically different fibril structures. Our results demonstrate that the fibril fragmentation stabilities of these different α-synuclein fibril polymorphs are all highly length dependent but distinct, with both A30P and A53T α-synuclein fibrils displaying increased resistance towards sonication-induced fibril fragmentation compared with WT α-synuclein fibrils. These conclusions show that fragmentation stabilities of different amyloid fibril polymorph structures can be erse and suggest that the approach we report here will be useful in comparing the relative stabilities of amyloid fibril types or fibril polymorphs toward fragmentation under different biological conditions.
Publisher: Cold Spring Harbor Laboratory
Date: 26-12-2018
DOI: 10.1101/506386
Abstract: The ision of amyloid protein fibrils is required for the propagation of the amyloid state, and is an important contributor to their stability, pathogenicity and normal function. Here, we combine kinetic nano-scale imaging experiments with analysis of a mathematical model to resolve and compare the ision stability of amyloid fibrils. Our theoretical results show that the ision of any type of filament is uniquely described by a set of three characteristic properties, resulting in convergence to self-similar length distributions distinct to each fibril type and conditions applied. By applying these results to profile the dynamical stability towards breakage for four different amyloid types, we reveal particular differences in the ision properties of disease-related amyloid formed from alpha-synuclein compared with non-disease associated model amyloid, the former showing lowered intrinsic stability towards breakage and increased likelihood of shedding smaller particles. Our results enable the comparison of protein filaments’ intrinsic dynamic stabilities, which are key to unravelling their toxic and infectious potentials.
Publisher: Wiley
Date: 11-02-2015
DOI: 10.1111/MMI.12930
Publisher: Elsevier BV
Date: 11-2011
Publisher: Proceedings of the National Academy of Sciences
Date: 22-03-2010
Abstract: Peroxiredoxins (Prxs) are ubiquitous antioxidants that protect cells against oxidative stress. We show that the yeast Tsa1/Tsa2 Prxs colocalize to ribosomes and function to protect the Sup35 translation termination factor against oxidative stress–induced formation of its heritable [ PSI + ] prion conformation. In a tsa1 tsa2 [ psi - ] [ PIN + ] strain, the frequency of [ PSI + ] de novo formation is significantly elevated. The Tsa1/Tsa2 Prxs, like other 2-Cys Prxs, have dual activities as peroxidases and chaperones, and we show that the peroxidase activity is required to suppress spontaneous de novo [ PSI + ] prion formation. Molecular oxygen is required for [ PSI + ] prion formation as growth under anaerobic conditions prevents prion formation in the tsa1 tsa2 mutant. Conversely, oxidative stress conditions induced by exposure to hydrogen peroxide elevates the rate of de novo [ PSI + ] prion formation leading to increased suppression of all three termination codons in the tsa1 tsa2 mutant. Altered translational fidelity in [ PSI + ] strains may provide a mechanism that promotes genetic variation and phenotypic ersity (True HL, Lindquist SL (2000) Nature 407:477–483). In agreement, we find that prion formation provides yeast cells with an adaptive advantage under oxidative stress conditions, as elimination of the [ PSI + ] prion from tsa1 tsa2 mutants renders the resulting [ psi - ] [ pin - ] cells hypersensitive to hydrogen peroxide. These data support a model in which Prxs function to protect the ribosomal machinery against oxidative damage, but when these systems become overwhelmed, [ PSI + ] prion formation provides a mechanism for uncovering genetic traits that aid survival during oxidative stress conditions.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 12-1991
DOI: 10.1016/0378-1119(91)90441-D
Abstract: A human eIF-2 alpha cDNA (encoding alpha-subunit of the eukaryotic initiation factor-2) was expressed under the control of the galactose-regulated GAL1, 10 promoter, in Saccharomyces cerevisiae, in order to study the possible interactions of human eIF-2 alpha with the yeast protein synthesis apparatus. Isoelectric focusing coupled with Western-blot analysis demonstrated that the human eIF-2 alpha subunit synthesized in yeast under a variety of growth conditions was detected as two bands which co-migrated with the phosphorylated and unphosphorylated forms of rabbit eIF-2 alpha, suggesting covalent modification in vivo. Cell fractionation studies further demonstrated that the synthesised human eIF-2 alpha protein, though present in the cytoplasm, was largely associated with the yeast ribosomes, but could be removed from these by washing with 0.3 M KCl. This possible association of the synthesised human subunit into a three-subunit (alpha, beta and gamma) eIF-2 complex was further examined by partial purification of the yeast eIF-2 complex and estimation of the molecular mass of this complex. Immunoreactive eIF-2 alpha was found in fractions with eIF-2 activity and the estimated molecular mass (130 kDa) corresponded to that predicted for the eIF-2 trimer. These analyses suggest that human eIF-2 alpha subunit synthesised in yeast can become involved with the yeast protein synthetic apparatus, though whether this is a functional incorporation requires further genetic studies.
Publisher: Elsevier BV
Date: 11-1999
Publisher: Springer Science and Business Media LLC
Date: 12-1988
DOI: 10.1007/BF00434078
Publisher: Springer Science and Business Media LLC
Date: 08-1994
DOI: 10.1007/BF00313794
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mick Tuite.