Abstract
Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.
Highlights
Transthyretin-related amyloidoses (ATTR amyloidosis) are characterized by extracellular deposition of insoluble TTR amyloid fibrils in several tissues, being polyneuropathy and cardiomyopathy the major clinical manifestations, as reviewed in [1,2]
We further explored the role of SerpinA1 on the in vitro and in vivo modulation of plasmin-mediated TTR proteolysis and how this modulation may impact TTR amyloidogenesis to contribute to the development of more targeted therapies for the treatment of ATTR amyloidosis
Previous studies revealed that to TTR S52P, recombinant TTR V30M was susceptible to plasmin-mediated proteolysis [22]
Summary
Transthyretin-related amyloidoses (ATTR amyloidosis) are characterized by extracellular deposition of insoluble TTR amyloid fibrils in several tissues, being polyneuropathy and cardiomyopathy the major clinical manifestations, as reviewed in [1,2]. The ubiquitous distribution of plasmin, its structural similarities to trypsin [22], and the reported activation of plasminogen activation system (PAS) in other amyloid-related disorders, such as Alzheimer’s disease [23] and immunoglobulin light chain (AL) amyloidosis [24,25,26] indicate that this protease could have a key role in TTR amyloidogenesis. The SerpinA1 mRNA was found to be differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients compared to healthy controls and, a high inverse correlation between SerpinA1 and TTR genes was observed. We further explored the role of SerpinA1 on the in vitro and in vivo modulation of plasmin-mediated TTR proteolysis and how this modulation may impact TTR amyloidogenesis to contribute to the development of more targeted therapies for the treatment of ATTR amyloidosis
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