Abstract
Familial amyloid polyneuropathy is a hereditary systemic amyloidosis caused by a mutation in the transthyretin (TTR) gene. Amyloid deposits in tissues of patients contain not only full-length TTR but also C-terminal TTR fragments. However, in vivo models to evaluate the pathogenicity of TTR fragments have not yet been developed. Here, we generated transgenic Caenorhabditis elegans strains expressing several types of TTR fragments or full-length TTR fused to enhanced green fluorescent protein in the body wall muscle cells and analyzed the phenotypes of the worms. The transgenic strain expressing residues 81–127 of TTR, which included the β-strands F and H, formed aggregates and caused defective worm motility and a significantly shortened lifespan compared with other strains. These findings suggest that the C-terminal fragments of TTR may contribute to cytotoxicity of TTR amyloidosis in vivo. By using this C. elegans model system, we found that (−)-epigallocatechin-3-gallate, a major polyphenol in green tea, significantly inhibited the formation of aggregates, the defective motility, and the shortened lifespan caused by residues 81–127 of TTR. These results suggest that our newly developed C. elegans model system will be useful for in vivo pathological analyses of TTR amyloidosis as well as drug screening.
Highlights
Hereditary transthyretin (ATTRm) amyloidosis, called transthyretin (TTR)-related familial amyloid polyneuropathy (TTR-FAP), is a fatal inherited disease associated with extracellular amyloid deposits derived from TTR1
We describe a Caenorhabditis elegans model that expresses various TTR fragments to elucidate the pathogenesis of C-terminal fragments of TTR in vivo, and we established this model as a tool for screening drug candidates for TTR amyloidosis
To investigate the pathogenesis of C-terminal fragments of TTR in vivo, we generated a C. elegans model expressing various TTR fragments fused to enhanced green fluorescent protein (EGFP): the full-length wild-type TTR (TTRWT::EGFP), the 1–80 residue fragment (TTR1–80::EGFP), the 49–127 residue fragment (TTR49–127::EGFP), the 81–127 residue fragment (TTR81–127::EGFP), the full-length TTR but containing a Val30Met mutation (TTRV30M::EGFP), and EGFP alone (EGFP) as a control
Summary
Hereditary transthyretin (ATTRm) amyloidosis, called transthyretin (TTR)-related familial amyloid polyneuropathy (TTR-FAP), is a fatal inherited disease associated with extracellular amyloid deposits derived from TTR1. Liver transplantation is the most common treatment for patients with ATTRm. Dissociation of the TTR tetramer into monomers is the rate-limiting step in amyloid fibril formation[5]. Amyloid deposits in the tissues of ATTR amyloidosis consist of full-length TTR and C-terminal TTR fragments, especially the fragment with residues 49–127 (TTR49–127)[12,13,14,15]. Many attempts have been made to develop an animal model of TTR amyloidosis to clarify the molecular mechanism of the pathogenesis of this disease and to evaluate the therapeutic effects of candidate drugs[19]. We describe a Caenorhabditis elegans model that expresses various TTR fragments to elucidate the pathogenesis of C-terminal fragments of TTR in vivo, and we established this model as a tool for screening drug candidates for TTR amyloidosis
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