Research ArticleHEREDITARY AMYLOIDOSIS

Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients

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Science Translational Medicine  13 Sep 2017:
Vol. 9, Issue 407, eaam7621
DOI: 10.1126/scitranslmed.aam7621

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Marking misfolded proteins

Hereditary transthyretin amyloidosis is a systemic disease characterized by genetic mutations in transthyretin that cause misfolding and accumulation of transthyretin in amyloid deposits. Heart, eye, kidney, and brain tissue can be affected, leading to progressive organ dysfunction. Schonhoft et al. designed peptide probes that detected misfolded transthyretin oligomers in plasma samples from patients with hereditary amyloidosis with predominantly nervous system phenotypes. Treatment with a transthyretin kinetic stabilizer reduced the amount of misfolded oligomers. These transthyretin oligomer–specific probes may aid in earlier diagnosis and help unravel the mechanism of pathogenesis of hereditary amyloidosis.

Abstract

Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure-based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant–mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.

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