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

Abstract

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

<p>Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care</p>

“…76 This procedure, that replaces the mutant TTR protein with the wild-type protein, can indeed fail to stop subsequent progressive cardiac deposition. 77,78 Clinical observations post-liver transplantation suggest that preformed fibrils present in the organs of hATTR patients at the time of surgery could template and accelerate polymerization of soluble circulating TTR: it is hypothesized that this "seeding" may contribute to cardiomyopathy by cardiac deposition of wildtype TTR secreted by the new liver. 77…”

“…79 However, TTR stabilizers do not inhibit "seeding" of ATTR: this data may help to explain results of clinical trials. 78 Two drugs that act as TTR stabilizers have been assessed in controlled trials in hATTR amyloidosis:…”

The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin

“…TTR aggregation assay. TTR aggregation assays were performed as previously described [28]. Briefly, 1 mg/ml TTR sample in 10 mM Sodium Acetate pH 4.3, 100 mM KCl, 10 mM EDTA was incubated at 37° C during a maximum of 7 days.…”

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

“…Peptide systems, short peptides in particular, have already been employed as potential inhibitors of protein aggregation in a number of pathological conditions involving pathological protein aggregation [123][124][125][144][145][146]. The advantages associated with the use of short peptides include low overall toxicity resulting from the compatibility of peptide inhibitors with living tissues as opposed to small molecule inhibitors.…”