Abstract
Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the “molecular tweezers”, CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer’s disease and Parkinson’s disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-013-0256-8) contains supplementary material, which is available to authorized users.
Highlights
Transthyretin (TTR) is a 55-kDa tetramer made of identical subunits of 127 amino acids and contains an extensive β-sheet structure [1]
The cells were grown in the absence or presence of CLR01 or of Epigallocatechin gallate (EGCG), which has previously been found to be a potent inhibitor of to control at μM (TTR) aggregation [20,21]
Over the last few years, many small compounds have been proposed as disease-modifying therapeutic agents specific for TTR-related amyloidosis
Summary
Transthyretin (TTR) is a 55-kDa tetramer made of identical subunits of 127 amino acids and contains an extensive β-sheet structure [1]. TTR has two identical inner T4 binding sites located at the dimer–dimer interface. TTR carries about 15 % of total T4 in the plasma, more than 99 % of the T4-binding sites remain unoccupied [1]. More than 100 TTR single point mutations have been reported, most of them associated with abnormal TTR misfolding and self-assembly into amyloid fibrils that display distinct patterns of organ involvement, age of onset, and clinical course. Substitution of methionine for valine at position 30 of TTR (TTR V30M) results from the most common mutation associated with familial amyloidotic polyneuropathy (FAP), a multivisceral and life-threatening disease affecting predominantly the peripheral (PNS) and autonomic nervous system [2,3]. FAP presents a wide geographic distribution, with the largest populations in Portugal, Japan, and Sweden, and is estimated to affect ∼5000–10,000 patients worldwide [4]
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