Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

Miller, Sean R; Sekijima, Yoshiki; Kelly, Jeffery W.

doi:10.1038/labinvest.3700059

Cited by 182 publications

(176 citation statements)

References 40 publications

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“…However, it should be noted that these are practical limitations based on experimental considerations and are not indicative of theoretical shortcomings. In addition, our results are in qualitative accord with complementary analyses that have suggested a stabilizing effect of S-sulfonation and diflunisal and a destabilizing effect of S-cysteinylation on wildtype TTR structure under denaturing conditions (31,47).…”

Section: Discussionsupporting

confidence: 90%

“…TTR aggregation has been a model system for this approach, because small molecules, including the nonsteroidal anti-inflammatory drug diflunisal and many of its derivatives, are reported to stabilize the native tetrameric structure (31,32,46). In this study, we directly investigated the effect of diflunisal on F-rTTR tetramer structure by analysis of the s isotherms in the presence and absence of drug.…”

Section: Discussionmentioning

confidence: 99%

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The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Kingsbury

Laue

Klimtchuk

et al. 2008

Journal of Biological Chemistry

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Transthyretin (TTR) is normally a stable plasma protein.However, in cases of familial TTR-related amyloidosis and senile systemic amyloidosis (SSA), TTR is deposited as amyloid fibrils, leading to organ dysfunction and possibly death. The mechanism by which TTR undergoes the transition from stable, soluble precursor to insoluble amyloid fibril and the factors that promote this process are largely undetermined. Most models involve the dissociation of the native TTR tetramer as the initial step. It is largely accepted that the TTR gene mutations associated with TTR-related amyloidosis lead to the expression of variant proteins that are intrinsically unstable and prone to aggregation. It has been suggested that amyloidogenicity may be conferred to wild-type TTR (the form deposited in SSA) by chemical modification of the lone cysteine residue (Cys 10 ) through mixed disulfide bonds. S-Sulfonation and S-cysteinylation are prevalent TTR modifications physiologically, and studies have suggested their ability to modulate the structure of TTR under denaturing conditions. In the present study, we have used fluorescencedetected sedimentation velocity to determine the effect of S-sulfonate and S-cysteine on the quaternary structural stability of fluorophore-conjugated recombinant TTR under nondenaturing conditions. We determined that S-sulfonation stabilized TTR tetramer stability by a factor of 7, whereas S-cysteinylation enhanced dissociation by 2-fold with respect to the unmodified form. In addition, we report the direct observation of tetramer stabilization by the potential therapeutic compound diflunisal. Finally, as proof of concept, we report the sedimentation of TTR in serum and the qualitative assessment of the resulting data.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Kingsbury

Laue

Klimtchuk

et al. 2008

Journal of Biological Chemistry

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“…We have reported the efficacy of diflunisal, a nonsteroidal anti-inflammatory drug, for the inhibition of TTR amyloidogenesis (56). Although this compound shows promise in a normal human subjects oral dosing study (Y. Sekijima and J.W.K., unpublished results), it may be problematic for the treatment of V122I familial amyloid cardiomyopathy owing to compromised renal blood flow in the African American population, which suffers from a much higher incidence of kidney disease and failure (U.S. Renal Data System database, www.…”

Section: Discussionmentioning

confidence: 99%

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Green

Foss

Kelly

2005

Proc. Natl. Acad. Sci. U.S.A.

110

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The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K d1 ‫؍‬ 40 nM, Kd2 ‫؍‬ 1.4 M). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements.amyloidogenesis inhibitor ͉ kinetic stabilization F or many years nutritionists and dieticians have noted the health benefits of a soy-based diet, citing the much lower incidence of cancer, including breast cancer, in Asian countries (1-4). The isoflavone genistein (compound 1 in Fig. 1), found in various soy foods at concentrations of 1.9-229 g͞g, is the component of soy implicated in cancer chemoprevention (5). An additional 71-968 g͞g of genistein is present as its O-glucoside conjugate, genistin (2), which is rapidly deglycosylated by intestinal bacteria in vivo. Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6, 7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11-13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.Transthyretin (TTR) is a tetrameric protein composed of identical 127-aa ␤-sheet sandwich subunits (14, 15). TTR functions to transport holo-retinol-binding protein and thyroxine (T4) in the blood and cerebrospinal fluid (16,17). Under denaturing con...

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“…Various inhibitors acting in the initial stages of amyloid ␤ (A␤) fibril formation have been reported (13)(14)(15). Drugs that increase the stability of the native state and/or kinetic barrier to amyloid fibrils have been developed for transthyretin amyloidoses (16,17). However, the development of a novel strategy for destroying preformed amyloid fibrils is also desired.…”

mentioning

confidence: 99%

Destruction of Amyloid Fibrils of Keratoepithelin Peptides by Laser Irradiation Coupled with Amyloid-specific Thioflavin T

Ozawa

Kaji

Yagi

et al. 2011

Journal of Biological Chemistry

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Mutations in keratoepithelin are associated with blinding ocular diseases, including lattice corneal dystrophy type 1 and granular corneal dystrophy type 2. These diseases are characterized by deposits of amyloid fibrils and/or granular non-amyloid aggregates in the cornea. Removing the deposits in the cornea is important for treatment. Previously, we reported the destruction of amyloid fibrils of ␤ 2 -microglobulin K3 fragments and amyloid ␤ by laser irradiation coupled with the binding of an amyloid-specific thioflavin T. Here, we studied the effects of this combination on the amyloid fibrils of two 22-residue fragments of keratoepithelin. The direct observation of individual amyloid fibrils was performed in real time using total internal reflection fluorescence microscopy. Both types of amyloid fibrils were broken up by the laser irradiation, dependent on the laser power. The results suggest the laser-induced destruction of amyloid fibrils to be a useful strategy for the treatment of these corneal dystrophies.A number of proteins and peptides have been found to aggregate into insoluble amyloid fibrils that are involved in various diseases, including Alzheimer's disease, Parkinson's disease, and dialysis-related amyloidosis (1-5). Keratoepithelin is one of the amyloidogenic proteins responsible for blinding corneal dystrophies (6 -9). Although precursor proteins range from native globular proteins to unstructured peptides, the resultant amyloid fibrils have many characteristics in common (1-4). Amyloid fibrils are typically long, unbranched, and often twisted, consisting of several protofilaments. X-ray fiber diffraction experiments have shown that they are commonly constructed from ordered ␤-strands. The basic structure has been considered a cross-␤ structure in which the ␤-strands are located perpendicular to the fibril axis. In addition, amyloid fibrils exhibit specific optical behavior such as green birefringence when bound to the dye Congo red. They also bind to the fluorescence dye thioflavin T (ThT) 3 , resulting in a characteristic fluorescence emission at 482-490 nm with an excitation maximum at 446 -455 nm (10, 11).Hereditary corneal dystrophies are characterized by the abnormal deposition of amyloid fibrils and/or granular aggregation in the cornea (6 -9). Mutations of keratoepithelin, an extracellular matrix protein composed of 683 amino acids, also known as transforming growth factor ␤-induced (TGF␤I), are responsible for the dystrophies. Population analyses have revealed two hot spots of mutation, Arg-124 and Arg-555, associated with corneal dystrophies (7, 12). Regarding Arg-124, four different mutations are associated with four different phenotypes. The R124C mutation has been linked with lattice corneal dystrophy type 1, R124H with granular corneal dystrophy type 2, R124L with granular corneal dystrophy type 3, and R124S with a variant of granular corneal dystrophy type 1. Despite numerous studies, an effective therapeutic approach for these corneal dystrophies has yet to be established (9).Re...

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Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants

Cited by 182 publications

References 40 publications

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Destruction of Amyloid Fibrils of Keratoepithelin Peptides by Laser Irradiation Coupled with Amyloid-specific Thioflavin T

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