Potential treatment of transthyretin-type amyloidoses by sulfite

Altland, Klaus; Winter, Pia

doi:10.1007/s100480050081

Cited by 41 publications

(42 citation statements)

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“…4A) is quite similar with that of monomers with cysteinylated Cys10 [6]. Monomers with S-sulfonated Cys10 [16] or reduced Cys10 (after reaction with DTT) [6] are more stable. From these observations we conclude that the dimer conformational stability near neutral pH levels corresponds with monomer and tetramer conformational stability observed by IEF under partial denaturing conditions in the range of pH 5-5.7.…”

Section: Resultssupporting

confidence: 53%

“…2. We have demonstrated earlier that there is significant variability of the conformational monomer stability depending on differential ligands bound at Cys10-SH of the TTR monomer [6], that the ATTR-V30M mutation is a potent destabilizer of the folded monomeric structure [16], and that the genetic and nongenetic effects are additive. A sample from a heterozygote for normal TTR (N) and variant ATTR-V30M (V) contains three species of dimers NN, NV, and VV and all three dimers vary by different ligands bound at Cys10-SH.…”

Section: Discussionmentioning

confidence: 98%

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Polyacrylamide gel electrophoresis followed by sodium dodecyl sulfate gradient polyacrylamide gel electrophoresis for the study of the dimer to monomer transition of human transthyretin

Altland

Winter

2003

Electrophoresis

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Familial amyloidotic polyneuropathy (FAP) is caused by mutations which destabilize transthyretin (TTR) and facilitate the aggregation into extracellular amyloid fibrils preferentially in peripheral nerve and heart tissues. Therapeutic and preventive trials for FAP at the plasma TTR level require a careful study of the destabilization of TTR under variable conditions. We have developed a simple double one-dimensional (D1-D) electrophoretic procedure with polyacrylamide gel electrophoresis (PAGE) followed by sodium dodecylsulfate (SDS) gradient PAGE to study the dimer to monomer transition. TTR is first isolated by PAGE from other plasma proteins. The gel strip containing the TTR fraction is incubated in 2% SDS under varying conditions of temperature, buffer composition, pH, and additives like urea and/or a sulfhydryl-reactive agent, followed by SDS-gradient PAGE for the separation of TTR dimers and monomers. We demonstrate that an unidirectional dimer to monomer transition of normal TTR is achieved at 70-80 degrees C in neutral to mild alkaline buffers or at 37 degrees C and slightly acidic pH (6-7). Addition of urea favors the transition into monomers. Amyloidogenic mutations like amyloidogenic TTR (ATTR)-V30M or ATTR-I107V favor the transition into monomers in buffer systems close to the physiological pH of human plasma. We conclude that this finding has to be considered by any hypothesis on ATTR-derived amyloidogenesis.

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Section: Resultssupporting

confidence: 53%

Section: Discussionmentioning

confidence: 98%

Polyacrylamide gel electrophoresis followed by sodium dodecyl sulfate gradient polyacrylamide gel electrophoresis for the study of the dimer to monomer transition of human transthyretin

Altland

Winter

2003

Electrophoresis

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“…The most common exogenous source is sulfiting agents used as preservatives in dried fruits and vegetables (2) and in wine where millimolar concentrations have been reported (3). Sulfite is also used as a stabilizer in many drugs administered to patients (4). Interestingly, its presence in a dexamethasone preparation increased the neurotoxicity of excitotoxic agents (5) suggesting that it could have an effect on neuronal cells.…”

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confidence: 99%

A Mechanism of Sulfite Neurotoxicity

Zhang

Vincent

Halliwell

et al. 2004

Journal of Biological Chemistry

123

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Exposure of Neuro-2a and PC12 cells to micromolar concentrations of sulfite caused an increase in reactive oxygen species and a decrease in ATP. Likewise, the biosynthesis of ATP in intact rat brain mitochondria from the oxidation of glutamate was inhibited by micromolar sulfite. Glutamate-driven respiration increased the mitochondrial membrane potential (MMP), and this was abolished by sulfite but the MMP generated by oxidation of malate and succinate was not affected. The increased rate of production of NADH from exogenous NAD ؉ and glutamate added to rat brain mitochondrial extracts was inhibited by sulfite, and mitochondria preincubated with sulfite failed to reduce NAD ؉ . Glutamate dehydrogenase (GDH) in rat brain mitochondrial extract was inhibited dose-dependently by sulfite as was the activity of a purified enzyme. An increase in the K m (glutamate) and a decrease in V max resulting in an attenuation in V max /K m (glutamate) at 100 M sulfite suggest a mixed type of inhibition. However, uncompetitive inhibition was noted with decreases in both K m (NAD ؉ ) and V max , whereas V max /K m (NAD ؉ ) remained relatively constant. We propose that GDH is one target of action of sulfite, leading to a decrease in ␣-ketoglutarate and a diminished flux through the tricarboxylic acid cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a decreased MMP, and a decrease in ATP synthesis. Because glutamate is a major metabolite in the brain, inhibition of GDH by sulfite could contribute to the severe phenotype of sulfite oxidase deficiency in human infants.

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“…Sulfite is one of the few sulfating agents approved by the Food and Drug Administration as a food preservative and antioxidant to prevent or reduce spoilage [3]. It is also used as an ingredient of many medications, such as antibiotics, analgesics, and anesthetics [2,5,6]. It has been suggested that the presence of sulfite in dexamethasone preparations has increased its neurotoxicity of the preparation [73].…”

Section: Discussionmentioning

confidence: 99%

“…Sulfite is used as an antioxidant and preservative in dried fruits, vegetables, pickled onion, and beverages such as fruit juice, grape juice, beer, and wine to prevent or reduce spoilage [2][3][4]. Sulfite is also used as a stabilizer in many drugs and cosmetics [2,5,6]. For the majority of people, exposure to sulfites occurs during consumption of foods and drinks that contain sulfite preservative [2].…”

Section: Introductionmentioning

confidence: 99%