Biology subjects

Eisenberg, D.

Publications and source records attributed to Eisenberg, D..

3 recordsLinked to original sources

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↗

bioRxiv2018

Structural variability of EspG chaperones from mycobacterial ESX-1, ESX-3 and ESX-5 type VII secretion systems

Type VII secretion systems (ESX) are responsible for transport of multiple proteins in mycobacteria. How different ESX systems achieve specific secretion of cognate substrates remains elusive. In the ESX systems, the cytoplasmic chaperone EspG forms complexes with heterodimeric PE-PPE substrates that are secreted from the cells or remain associated with the cell surface. Here we report the crystal structure of the EspG1 chaperone from the ESX-1 system determined using a fusion strategy with T4 lysozyme. EspG1 adopts a quasi 2-fold symmetric structure that consists of a central {beta}-sheet and two -helical bundles. Additionally, we describe the structures of EspG3 chaperones from four different crystal forms. Alternate conformations of the putative PE-PPE binding site are revealed by comparison of the available EspG3 structures. Analysis of EspG1, EspG3 and EspG5 chaperones using small-angle X-ray scattering (SAXS) reveals that EspG1 and EspG3 chaperones form dimers in solution, which we observed in several of our crystal forms. Finally, we propose a model of the ESX-3 specific EspG3-PE5-PPE4 complex based on the SAXS analysis.\n\nHighlightsO_LIThe crystal structure of EspG1 reveals the common architecture of the type VII secretion system chaperones\nC_LIO_LIStructures of EspG3 chaperones display a number of conformations that could reflect alternative substrate binding modes\nC_LIO_LIEspG3 chaperones dimerize in solution\nC_LIO_LIA model of EspG3 in complex with its substrate PE-PPE dimer is proposed based on SAXS data\nC_LI

biochemistry↗