Systemic amyloid diseases such as the transthyretin (TTR) amyloidoses are a class of devastating disorders caused by the pathologic aggregation and deposition of specific destabilized proteins as amyloid fibrils on tissues distal from the site of protein synthesis. Currently, no non-invasive therapies exist to treat the majority of these diseases, making systemic amyloidoses a large unmet medical need. A primary factor defining the pathologic extracellular protein aggregation central to these disorders is the secretion of destabilized, amyloidogenic proteins from effector tissues such as the liver. The efficient secretion of these proteins increases serum concentrations of amyloidogenic protein available for pathologic, concentration-dependent aggregation, directly impacting disease pathogenesis in patients. Clinical results from liver transplant recipients show that reducing serum concentrations of amyloidogenic proteins can decrease pathologic protein aggregation, attenuate peripheral proteotoxicity and improve prognosis for patients presenting with a variety of distinct systemic amyloidoses. We hypothesize that activating the endogenous Unfolded Protein Response (UPR) signaling pathways that regulate protein secretion from effector tissues is a non-invasive strategy to similarly decrease secretion and reduce extracellular concentrations of amyloidogenic proteins available for pathologic extracellular aggregation. Consistent with this prediction, we show that activating the UPR- associated transcription factor ATF6 reduces secretion of destabilized, amyloidogenic TTR mutants, but does not affect the secretion of wild-type TTR or the endogenous secreted proteome. Here, we employ TTR as a model amyloidogenic protein to show that ATF6 activation has therapeutic potential to reduce pathologic extracellular aggregation and proteotoxicity of amyloidogenic TTR mutants using a novel patient-derived, multi- system induced pluripotent stem cell model of TTR amyloid disease that recapitulates nearly all aspects of TTR amyloid disease pathology observed in patients. Furthermore, we are extending this analysis to show that ATF6 activation similarly reduces the secretion and proteotoxicity of amyloidogenic proteins involved in other systemic amyloid diseases including Light Chain Amyloidosis - an acquired systemic amyloid disease that affects >1 million individuals worldwide. Through these efforts, we will show that the stress-independent activation of UPR-associated signaling pathways such as that regulated by ATF6 is a broadly-applicable therapeutic strategy to reduce the secretion and pathologic extracellular aggregation of amyloidogenic proteins associated with multiple systemic amyloid diseases. These results will further motivate our ongoing high- throughput screening efforts to identify ATF6 activators, as a single small molecule ATF6 activator has the potential to treat multiple systemic amyloidoses (i.e. a one-drug:multiple-disease therapeutic paradigm) dramatically improving the economics of translating selective ATF6 activators into the clinic to ameliorate pathologic extracellular aggregation associated with these diseases.

Public Health Relevance

Systemic amyloid diseases are a devastating class of human diseases caused by the pathologic, concentration-dependent aggregation of specific proteins into proteotoxic soluble aggregates and amyloid fibrils that deposit in tissues distal from the sit of protein synthesis. Significant genetic and clinical evidence shows that a primary determinant in defining pathologic distal protein aggregation critical for disease pathogenesis is the secretio of destabilized, amyloidogenic proteins from the site of synthesis. Here, we show that activation of endogenous stress-responsive signaling pathways that regulate protein secretion through the secretory pathway is a broadly-applicable therapeutic strategy to selectively reduce secretion of destabilized, amyloidogenic proteins, decrease serum concentrations of amyloidogenic protein available for aggregation, and attenuate pathologic protein aggregation associated with multiple systemic amyloid disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Rasooly, Rebekah S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Giadone, Richard M; Rosarda, Jessica D; Akepati, Prithvi Reddy et al. (2018) A library of ATTR amyloidosis patient-specific induced pluripotent stem cells for disease modelling and in vitro testing of novel therapeutics. Amyloid 25:148-155
Chen, Kai-Chun; Qu, Song; Chowdhury, Saikat et al. (2017) The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer. EMBO J 36:2296-2309
Plate, Lars; Wiseman, R Luke (2017) Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy. Trends Cell Biol 27:722-737
Plate, Lars; Cooley, Christina B; Chen, John J et al. (2016) Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. Elife 5:
Chen, John J; Genereux, Joseph C; Suh, Eul Hyun et al. (2016) Endoplasmic Reticulum Proteostasis Influences the Oligomeric State of an Amyloidogenic Protein Secreted from Mammalian Cells. Cell Chem Biol 23:1282-1293
Rainbolt, T Kelly; Lebeau, Justine; Puchades, Cristina et al. (2016) Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress. Cell Rep 14:2041-2049
Leung, Amy; Murphy, George J (2016) Multisystemic Disease Modeling of Liver-Derived Protein Folding Disorders Using Induced Pluripotent Stem Cells (iPSCs). Methods Mol Biol 1353:261-70
Lindberg, Iris; Shorter, James; Wiseman, R Luke et al. (2015) Chaperones in Neurodegeneration. J Neurosci 35:13853-9
Genereux, Joseph C; Qu, Song; Zhou, Minghai et al. (2015) Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J 34:4-19
Genereux, Joseph C; Wiseman, R Luke (2015) Regulating extracellular proteostasis capacity through the unfolded protein response. Prion 9:10-21

Showing the most recent 10 out of 12 publications