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Abstract: Transthyretin (TTR) amyloid fibril formation, which is triggered by the dissociation of tetrameric TTR, appears to be the causative factor in familial amyloidotic polyneuropathy and senile systemic amyloidosis. Binding of thyroxine (T4), a native ligand of TTR, stabilizes the tetramer, but the bioavailability of T4 for TTR binding is limited due to the preferential binding of T4 to globulin, the major T4 carrier in plasma. Here, we show that Cr3+ increased the T4-binding capacity of wild-type (WT) and amyloidogenic V30M-TTR. Moreover, we demonstrate that Cr3+ and T4 cooperatively suppressed in vitro fibril formation due to the stabilization of WT-TTR and V30M-TTR. [Copyright &y& Elsevier]

Transthyretin-related amyloidosis is a slowly progressive disorder caused by deposition of insoluble amyloid plaques formed by fibrillization of mutant or defective transthyretin (TTR) monomers that leads to neurodegeneration and organ failure. Thus, any compound exhibiting TTR amyloid formation inhibitory activity or TTR amyloid fibril disrupting activity might be a potential candidate for the development of therapies for these disorders. Our aim in this study was the evaluation of the TTR amyloid fibril disrupting potential of extracts of leaves and immature fruits of two Juglans plants, i.e., Juglans mandshurica var. sachalinensis and Juglans mandshurica var. cordiformis. The TTR amyloid fibril disrupting activity was measured by Thioflavin-T (ThT) assay and PROTEOSTAT® Protein aggregation assay methods. A fifty percent acetone extract of the fruits of Juglans mandshurica var. cordiformis showed strong amyloid fibril disrupting activity, and was further fractionated using different solvents. Ethyl acetate and n-butanol fractions showed significant activity in both assays. Syringic acid was isolated and identified as main compound in both of these fractions; however, it did not show any activity. Furthermore, some of the previously reported compounds from Juglans plants including naphthoquinone derivatives and phenolic compounds were evaluated to identify the potential bioactive compounds. Among them, juglone, a naphthoquinone derivative showed promising activity. However, juglone also showed strong cytotoxicity in HEK293 cells. Thus, future studies should focus on the isolation and identification of naphthoquinone derivatives or other compounds from Juglans plan ts with potent bioactivity and low cytotoxicity. [ABSTRACT FROM AUTHOR]

Amyloid fibril formation of mutant transthyretin (TTR) that causes familial amyloid polyneuropathy occurs in the extracellular space. Thus, secretion of TTR variants contributes to the pathogenesis of amyloidosis. However, the molecular mechanisms underlying the endoplasmic reticulum (ER) exit or retention and subsequent degradation of TTR variants remain unclear. Here, we demonstrated that the nonsecreted TTR variants, such as D18G TTR and amyloidogenic TTRs with introduced monomeric mutation (M-TTRs), stably interact with the ER chaperone BiP in mammalian cells. These proteins were co-secreted with the secreted form of BiP in which the KDEL signal was removed, indicating that BiP partially contributes to the ER retention of nonsecreted TTR variants. More interestingly, the degradation efficiency of nonsecreted TTRs was increased when BiP was down-regulated by small interfering RNA. Thus, BiP protects the TTR variants from immediate degradation. Additionally, we showed that the stability of nonsecreted TTR variants is not disturbed in the coat complex Il-deficient conditions, which are enough to inhibit the ER export of secreted TTR variants, including wild-type TTR. Therefore, the post-ER retrieval mechanism might not contribute to the ER-associated degradation of nonsecreted TTR variants. These findings suggest that the affinity to the ER-resident protein BiP regulates the fate of TTR variants in the ER. [ABSTRACT FROM AUTHOR]