The systemic amyloidoses are diverse disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream tissues. Although well described clinically, the contribution of synthesizing organs to amyloid disease pathogenesis is unknown. Here, we utilize hereditary transthyretin amyloidosis (ATTR amyloidosis) induced pluripotent stem cells (iPSCs) to define the contribution of hepatocyte-like cells (HLCs) to the proteotoxicity of secreted transthyretin (TTR). To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We combined this tool with single-cell RNA sequencing to identify hepatic proteostasis factors correlating with destabilized TTR production in iPSC-derived HLCs. By generating an ATF6 inducible patient-specific iPSC line, we demonstrated that enhancing hepatic ER proteostasis preferentially reduces the secretion of amyloidogenic TTR. These data highlight the liver's capacity to chaperone misfolded TTR prior to deposition, and moreover suggest the potential for unfolded protein response modulating therapeutics in the treatment of diverse systemic amyloidoses.
A singular gene-editing strategy can correct all mutations in ATTR amyloidosis
Mutant TTR iPSC-derived hepatic cells employ ER stress and proteostasis machinery
Hepatic cells of ATTR amyloidosis patients exhibit cellular and molecular changes
ATF6 branch-specific activation of the UPR reduces secretion of proteotoxic TTR
In this article, Giadone and colleagues identify proteostasis factors, including the unfolded protein response (UPR), that drive response to systemic amyloid disease in patient-specific iPSCs. This work demonstrates that stress-independent, selective activation of the adaptive UPR is capable of selectively reducing the secretion of toxic, destabilized protein.