Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant disorder characterized by systemic extracellular deposition of transthyretin (TTR
As part of a study on tissue uptake of thyroxine (T4) in a transthyretin (TTR)-null mouse strain, kinetic parameters of thyroxine metabolism in wild-type mice under normal physiological conditions are presented. Kinetic analysis of injected [(125)I]T4 showed that TTR-null mutants have markedly increased [(125)I]T4 transfer rate constants from plasma to the fast-exchange compartments of liver and kidney and from fast to slow kidney compartments. Transfer rates from plasma to brain, testes, and fat were little affected. The T4 tissue content in the mutants was greatly reduced in brain but relatively normal in liver and kidney. No major changes were observed in brain 3,3',5-triiodothyronine concentrations, suggesting that availability of this hormone is not markedly altered in the mutant mice. The low T4 brain content probably reflects the absence of T4-TTR complexes in the mutant choroid plexus and cerebrospinal fluid. This study indicates that TTR is not essential for T4 tissue uptake or for T4 to reach the brain across the choroid plexus-cerebrospinal fluid and/or blood-brain barriers.
Transthyretin (TTR) is a tetrameric protein synthesized mainly by the liver and the choroid plexus, from where it is secreted into the plasma and the cerebrospinal fluid, respectively. Some forms of polyneuropathy, vitreopathy, and cardiomyopathy are caused by the deposition of normal and/or mutant TTR molecules in the form of amyloid fibrils. Familial amyloidotic polyneuropathy is the most common form of TTR amyloidosis related to the V30M variant. It is still unclear the process by which soluble proteins deposit as amyloid. The treatment of amyloid-related disorders might attempt the stabilization of the soluble protein precursor to retard or inhibit its deposition as amyloid; or aim at the resorption of the deposited amyloid. The anthracycline 4'-iodo-4'-deoxydoxorubicin (I-DOX) has been shown to reduce the amyloid load in immunoglobulin light-chain amyloidosis. We investigated 1) whether I-DOX has affinity for TTR amyloid in tissues, 2) determined the I-DOX binding constants to TTR synthetic fibrils, and 3) determined the nature of the effect of I-DOX on TTR fibrils. We report that 1) I-DOX co-localizes with amyloid deposits in tissue sections of patients with familial amyloidotic polyneuropathy; 2) I-DOX strongly interacts with TTR amyloid fibrils and presents two binding sites with k(d) of 1.5 x 10(-11) mol/L and 5.6 x 10(-10) mol/L, respectively; and 3) I-DOX disrupts the fibrillar structure of TTR amyloid into amorphous material, as assessed by electron microscopy but does not solubilize the fibrils as confirmed by filter assays. These data support the hypothesis that I-DOX and less toxic derivatives can prove efficient in the treatment of TTR-related amyloidosis.
Recently, a transthyretin variant, TTR Met 119, in which methionine substitutes for threonine 119, a component of the protein's iodothyronine binding site, was identified in individuals with transient euthyroid hyperthyroxinemia. Healthy carriers of Met 119 have normal serum thyroid hormone concentrations, but two studies of Met 119 carriers have differed as to whether T4 binding to TTR is increased. An additional kindred has been identified by hybrid isoelectric focusing in an ongoing screening program for TTR variants in the Portuguese population with TTR Met 30 associated familial amyloidotic polyneuropathy. Cyanogen bromide peptide mapping and DNA restriction length polymorphism analyses showed that the propositus was a compound heterozygote for two TTR variants: Asn 90 and Met 119. Family analysis revealed that he inherited the TTR Met 119 variant from the mother and the TTR Asn 90 variant from the father. Neither the compound heterozygote nor his parents had symptoms of familial amyloidotic polyneuropathy. Serum dialysis with stepwise saturation of iodothyronine binding sites confirmed that TTR binding of T4 is increased in TTR Met 119. The increased binding is due to a higher TTR concentration rather than an increased association constant for T4. Because of the small proportion of serum T4 bound by TTR, increased T4 binding by TTR did not affect the ratio of free to bound T4 or T4 concentrations. In contrast, plasma retinol binding protein, almost all of which is bound by TTR, was elevated. The Asn 90 mutation does not affect either the concentration or the hormone binding characteristics of the protein. Possible long-term effects of these mutations and the combined heterozygotic state remain to be determined.
The present study investigates the association of mutations in the nuclear receptor NR4A2 in schizophrenic patients. The human Nur-related receptor 1, NR4A2, is an orphan nuclear receptor that can be constitutively active as a transcription factor and for which no natural ligand has yet been identified. Alone or with retinoid X receptor, RXR, NR4A2 influences the expression of several genes important for human brain development and regulation. In the absence of Nurr1 (the mouse homologue to human NR4A2), ventral mesencephalic dopaminergic mouse neurons evidence severe developmental failure, a condition that is lethal soon after birth. Nurr1 involvement in the dopaminergic system makes it a good candidate for study in neuropsychiatric disorders such as schizophrenia and Parkinson disease. Evidence by others support this hypothesis (1) mapping of the NR4A2 gene to chromosome 2q22-23, a region with suggestive linkage to schizophrenia and (2) identification of mutations in patients with schizophrenia (c.366-369delTAC, c.308A > G, c.-469delG), manic depression (c.289A > G), and familial Parkinson's disease (c.-291delT, c.-245T > G). To further extend these observations, we searched for all these mutations in 176 Caucasian Portuguese and 82 Caucasian Brazilian subjects with lifetime diagnosis of schizophrenia. The study failed to identify any of the described mutations in patients or controls. Nevertheless, these negative results do not exclude altered expression of nuclear receptors in schizophrenia or the presence of other mutations.
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