Amyloid formation in rat transthyretin: effect of oxidative stress

Tajiri, Takahiro; Ando, Yumiko; Hata, Kanako; Kamide, Kaeko; Hashimoto, Motonori; Nakamura, Masaaki; Terazaki, Hisayasu; Yamashita, Taro; Kai, Hirofumi; Haraoka, Katsuki; Imasato, Akira; Takechi, Kazuo; Nakagawa, Kazuko; Okabe, Hiroaki; Ishizaki, Takashi

doi:10.1016/s0009-8981(02)00179-1

Cited by 16 publications

(11 citation statements)

References 47 publications

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“…Oxidation of TTR could lead to insufficient transport of retinol and thyroxine and the formation of amyloid fibrils. [31][32][33] Another interesting observation was an increase in the C-terminal truncation of ApoA1 and ␣Hb in the day 42 PRBC supernatants. This suggests that enzymes belonging to the carboxypeptidase family increase in activity during storage of PRBC units.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Storage on the Accumulation of Oxidative Biomarkers in Donated Packed Red Blood Cells

Rael

Bar-Or

Ambruso

et al. 2009

Journal of Trauma: Injury, Infection &Amp; Critical Care

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Section: Discussionmentioning

confidence: 99%

The Effect of Storage on the Accumulation of Oxidative Biomarkers in Donated Packed Red Blood Cells

Rael

Bar-Or

Ambruso

et al. 2009

Journal of Trauma: Injury, Infection &Amp; Critical Care

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“…Interestingly, glutathione and its thiol-containing fragments including cysteine and cysteinylglycine are all known to conjugate with TTR, implying that these modifications may originate from glutathione (50). Increasing oxidative stress in rats by administration of paraquat resulted in an increase of TTR amyloid deposition, relative to untreated rats, but no data on the redox status of Cys-10 were provided (51). Another case illustrating the importance of oxidative stress as a risk factor for amyloidosis comes from an autopsy report on an FAP patient with mutations in both TTR (V30M) and extracellular superoxide dismutase (Arg213Gly).…”

Section: Discussionmentioning

confidence: 99%

Cys-10 Mixed Disulfide Modifications Exacerbate Transthyretin Familial Variant Amyloidogenicity: A Likely Explanation for Variable Clinical Expression of Amyloidosis and the Lack of Pathology in C10S/V30M Transgenic Mice?

Zhang

2005

Biochemistry

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The marked variation in clinical expression and age of familial amyloid disease onset is not well understood. One possibility is that metabolite modification(s) of a disease-associated mutant protein can change the energetics and propensity for misfolding, influencing the disease course. Each subunit of the transthyretin (TTR) tetramer has a single Cys residue that can exist in the SH form or as a mixed disulfide with the amino acid Cys or the peptide glutathione or fragments of the latter. The stability and amyloidogenicity of the clinically most important TTR variants (V30M and V122I) in their SH oxidation state were compared with those of their mixed disulfide adducts. All the Cys-10 mixed disulfide conjugates exhibited substantially decreased protein stability (urea, pH 7) and a higher rate and extent of amyloidogenesis (slightly acidic conditions). We also investigated the amyloidogenicity and stability of a C10S/V30M TTR double mutant which lacks the ability to make mixed disulfides, but retains the disease-associated V30M mutation. Unlike V30M TTR, this double mutant is nonamyloidogenic in transgenic mice. Our in vitro data reveal that the C10S/V30M and V30M TTR homotetramers have identical amyloidogenicity and stability, implying that Cys-10 mixed disulfide formation enhances amyloidogenesis in V30M transgenic mice. Given the high proportion of TTR subunits having mixed disulfide modifications in human plasma ( approximately 50%), and the data within demonstrating their increased amyloidogenicity, we submit that disulfide metabolite modifications have the potential to influence the course of amyloidoses, including TTR amyloidoses caused by mutations.

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“…Remarkably, for both wild-type murine and rat TTR, which are not amyloidogenic (33,63), E 0 is estimated to be Ϫ5.83. The predicted intrinsic aggregation propensities of murine and rat TTR are thus strongly reduced relative to human TTR, yet remain rather high in absolute terms.…”

Section: Crystal Structures Of Amyloidogenic Ttr Variants At Neutralmentioning

confidence: 96%

Amyloidogenic Potential of Transthyretin Variants

Cendron

Trovato

Seno

et al. 2009

Journal of Biological Chemistry

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Human transthyretin (TTR) is an amyloidogenic protein whose mild amyloidogenicity is enhanced by many point mutations affecting considerably the amyloid disease phenotype. To ascertain whether the high amyloidogenic potential of TTR variants may be explained on the basis of the conformational change hypothesis, an aim of this work was to determine structural alterations for five amyloidogenic TTR variants crystallized under native and/or destabilizing (moderately acidic pH) conditions. While at acidic pH structural changes may be more significant because of a higher local protein flexibility, only limited alterations, possibly representing early events associated with protein destabilization, are generally induced by mutations. This study was also aimed at establishing to what extent wildtype TTR and its amyloidogenic variants are intrinsically prone to ␤-aggregation. We report the results of a computational analysis predicting that wild-type TTR possesses a very high intrinsic ␤-aggregation propensity which is on average not enhanced by amyloidogenic mutations. However, when located in ␤-strands, most of these mutations are predicted to destabilize the native ␤-structure. The analysis also shows that rat and murine TTR have a lower intrinsic ␤-aggregation propensity and a similar native ␤-structure stability compared with human TTR. This result is consistent with the lack of in vitro amyloidogenicity found for both murine and rat TTR. Collectively, the results of this study support the notion that the high amyloidogenic potential of human pathogenic TTR variants is determined by the destabilization of their native structures, rather than by a higher intrinsic ␤-aggregation propensity.Protein misfolding and aggregation are involved in the pathogenesis of particularly relevant human deposition diseases, known as amyloidoses. In such diseases, normally soluble proteins undergo misfolding and become insoluble, causing the extracellular deposition of fibrillar aggregates (for reviews, see Ref. 1, 2). To date, more than 40 distinct human proteins have been associated with amyloidoses. For some of such proteins, including transthyretin (TTR), 4 lysozyme, gelsolin, ApoAI, and ApoAII, fibrinogen A ␣-chain and cystatin C, the amyloidogenic potential is induced, or is enhanced as in the case of TTR (see below), by specific mutations. The most frequent hereditary amyloidoses are caused by the genetic variants of human TTR (2).TTR is a homotetramer of about 55 kDa involved in the transport of thyroxine in the extracellular fluids and in the cotransport of vitamin A, by forming a macromolecular complex with retinol-binding protein, the specific plasma carrier of retinol (3-5). Its three-dimensional structure is known at high resolution (6, 7). The structure is characterized by a large predominance of ␤-strands, and its four monomers are arranged according to a 222 symmetry, where one of the 2-fold symmetry axes of the molecule coincides with a long channel that transverses the entire tetramer and harbors two symmetrical bind...

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Amyloid formation in rat transthyretin: effect of oxidative stress

Cited by 16 publications

References 47 publications

The Effect of Storage on the Accumulation of Oxidative Biomarkers in Donated Packed Red Blood Cells

The Effect of Storage on the Accumulation of Oxidative Biomarkers in Donated Packed Red Blood Cells

Cys-10 Mixed Disulfide Modifications Exacerbate Transthyretin Familial Variant Amyloidogenicity: A Likely Explanation for Variable Clinical Expression of Amyloidosis and the Lack of Pathology in C10S/V30M Transgenic Mice?

Amyloidogenic Potential of Transthyretin Variants

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