Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Saelices, Lorena; Pokrzywa, Małgorzata; Pawelek, Katarzyna; Eisenberg, David

doi:10.1016/j.nbd.2018.09.007

Cited by 13 publications

(8 citation statements)

References 28 publications

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“…In our previous work on inhibition of TTR, we generated TTR peptide inhibitors that block both protein aggregation and amyloid seeding catalyzed by ex-vivo ATTR fibrils (3,10). Moreover, diseased flies showed motor improvement and a reduction of TTR deposition after treatment with our peptide inhibitors (28). In this study we expand the evaluation of peptide inhibitors to question their inhibitory capacity in comparison to two tetramer stabilizers and mutagenesis-based stabilization.…”

Section: Discussionmentioning

confidence: 96%

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Saelices

Chung

Lee

et al. 2018

Preprint

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Amyloid deposition of the hormone transporter transthyretin causes familial and sporadic amyloidoses. The current treatment for familial cases is gene-therapy by liver transplantation. However, this procedure is often insufficient to stop subsequent cardiac deposition. Our recent work has shown that preformed amyloid fibrils present in the heart by the time of surgery can template or seed further polymerization of native transthyretin. No drugs have been approved to stop or slow this seeding process; the only treatment option is heart transplantation. Here we explore two potential inhibitory mechanisms. Of clinical significance, we found that tetramer stabilization does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex-vivo fibrils efficiently inhibits amyloid seeding in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach to be further explored.

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Section: Discussionmentioning

confidence: 96%

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Saelices

Chung

Lee

et al. 2018

Preprint

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“…In our previous work on inhibition of TTR, we generated TTR peptide inhibitors that block both protein aggregation and amyloid seeding catalyzed by ex vivo ATTR fibrils (3,10). Moreover, diseased flies showed motor improvement and a reduction of TTR deposition after treatment with our peptide inhibitors (30). In this study, we expand the evaluation of peptide inhibitors to question their inhibitory capacity compared with two tetramer stabilizers and mutagenesis-based stabilization.…”

Section: Inhibition Of Amyloid Seedingmentioning

confidence: 97%

A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils

Saelices

Nguyen

Chung

et al. 2019

Journal of Biological Chemistry

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The tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and is secreted by the liver, choroid plexus, and retinal epithelium, respectively. Systemic amyloid deposition of aggregated transthyretin causes hereditary and sporadic amyloidoses. A common treatment of patients with hereditary transthyretin amyloidosis is liver transplantation. However, this procedure, which replaces the patient's variant transthyretin with the WT protein, can fail to stop subsequent cardiac deposition, ultimately requiring heart transplantation. We recently showed that preformed amyloid fibrils present in the heart at the time of surgery can template or seed further amyloid aggregation of native transthyretin. Here we assess possible interventions to halt this seeding, using biochemical and EM assays. We found that chemical or mutational stabilization of the transthyretin tetramer does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex vivo fibrils efficiently inhibits amyloid seeding by impeding self-association of the amyloiddriving strands F and H in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach. Transthyretin amyloidosis (ATTR) 2 is a fatal disease caused by the abnormal aggregation of the protein transthyretin (TTR). TTR, a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, is secreted by the liver, choroid plexus, and retinal epithelium, respectively. TTR amyloid

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“…Expression of the V30M TTR variant in flies led to similar outcomes associated to neurological impairment with evidence of Congo red positive deposits in the brain of the aged transgenic flies ( Berg et al, 2009 ). Studies conducted on transgenic strains of drosophila led also to the identification of peptides as potential inhibitors of TTR aggregation as they were able to delay ATTR progression in the flies whilst decreasing TTR deposition ( Saelices et al, 2018 ).…”

Section: Animal Models Of Ttrmentioning

confidence: 99%

Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms

Faravelli

Mondani

Mangione

et al. 2022

Front. Mol. Biosci.

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The globular to fibrillar transition of proteins represents a key pathogenic event in the development of amyloid diseases. Although systemic amyloidoses share the common characteristic of amyloid deposition in the extracellular matrix, they are clinically heterogeneous as the affected organs may vary. The observation that precursors of amyloid fibrils derived from circulating globular plasma proteins led to huge efforts in trying to elucidate the structural events determining the protein metamorphosis from their globular to fibrillar state. Whereas the process of metamorphosis has inspired poets and writers from Ovid to Kafka, protein metamorphism is a more recent concept. It is an ideal metaphor in biochemistry for studying the protein folding paradigm and investigating determinants of folding dynamics. Although we have learned how to transform both normal and pathogenic globular proteins into fibrillar polymers in vitro, the events occurring in vivo, are far more complex and yet to be explained. A major gap still exists between in vivo and in vitro models of fibrillogenesis as the biological complexity of the disease in living organisms cannot be reproduced at the same extent in the test tube. Reviewing the major scientific attempts to monitor the amyloidogenic metamorphosis of globular proteins in systems of increasing complexity, from cell culture to human tissues, may help to bridge the gap between the experimental models and the actual pathological events in patients.

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Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Cited by 13 publications

References 28 publications

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils

Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms

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