Hepatocyte-like cells reveal novel role of SerpinA1 in transthyretin amyloidosis

Transthyretin (TTR)-related familial amyloid polyneuropathy (ATTR) results from aggregation and extracellular disposition of misfolded TTR variants. Growing evidence suggests the importance of hepatic chaperones for modulation of pathogenesis. We took advantage of iPSC-derived hepatocyte-like cells (HLCs) derived from ATTR patients (ATTR-HLCs) to compare chaperone gene expression to healthy individuals (H-HLCs). From the set of genes analyzed, chaperones that are predominantly located extracellularly were differently expressed. Expression of the chaperones showed a high correlation with TTR in both ATTR-HLCs and H-HLCs. In contrast, after TTR knockdown, the correlation was mainly affected in ATTR-HLCs suggesting that variant TTR expression triggers abberant chaperone expression. Serpin peptidase inhibitor clade A member 1 (SERPINA1/alpha-1 antitrypsin) was the only extracellular chaperone that was markedly upregulated after TTR knockdown in ATTR-HLCs. Co-immunoprecipitation revealed that SerpinA1 physically interacts with TTR. In vitro assays indicated that SerpinA1 can interfere with TTR aggregation. Taken together, our results suggest that extracellular chaperones play a crucial role in ATTR pathogenesis, in particular SerpinA1, which may affect amyloid formation.