Saelices, L. | Search bioRxiv

bioRxiv2018

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

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.

biochemistry↗

bioRxiv2018

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

Transthyretin amyloidosis (ATTR) is a fatal disease caused by the systemic aggregation and deposition of transthyretin (TTR), a blood transporter that is mainly produced in the liver. TTR deposits are made of elongated amyloid fibrils that interfere with normal tissue function leading to organ failure. The current standard care for hereditary neuropathic ATTR is liver transplantation or stabilization of the native form of TTR by tafamidis. In our previous work, we explored an additional strategy to halt protein aggregation by capping pre-existing TTR fibrils with structure-based designed peptide inhibitors. Our best peptide inhibitor TabFH2 has shown to be effective at inhibiting not only TTR aggregation but also amyloid seeding driven by fibrils extracted from ATTR patients. Here we evaluate the effects of peptide inhibitors in two Drosophila models of neuropathic ATTR and compared their efficacy with diflunisal, a protein stabilizer currently used off-label for the treatment of ATTR. Our peptide inhibitor TabFH2 was found the most effective treatment, which resulted in motor improvement and the reduction of TTR deposition. Our in vivo study shows that inhibiting TTR deposition by peptide inhibitors may represent a therapeutic strategy for halting the progression of ATTR.\n\nSIGNIFICANCE STATEMENTFamilial Amyloid Polyneuropathy (FAP) is a hereditary condition caused by the deposition of transthyretin (TTR) in nerves. Marked by progressive deficit and disability, FAP has no cure and limited therapeutic options. The replacement of the production source of mutant TTR by liver transplantation and the stabilization of native TTR by compounds, current lines of treatment, often fail to halt disease progression. Previously, we discovered that two segments of TTR drive amyloid deposition, and designed structure-based peptide inhibitors. Here we evaluate these peptide inhibitors in FAP models of Drosophila. The most efficient inhibitor resulted in an improvement of locomotor abilities and a reduction of TTR deposition. This study points to peptide inhibitors as a potential therapeutic strategy for FAP.

neuroscience↗