Expression of Amyloidogenic Transthyretin Drives Hepatic Proteostasis Remodeling in an Induced Pluripotent Stem Cell Model of Systemic Amyloid Disease

Giadone, Richard M.; Liberti, Derek C.; Matte, Taylor; Rosarda, Jessica D.; Ghosh, Sabrina; Diedrich, Jolene K.; Pankow, Sandra; Skvir, Nicholas; Jean, Jyh‐Chang; Yates, John R.; Wilson, Andrew; Connors, Lawreen H.; Kotton, Darrell N.; Wiseman, R. Luke; Murphy, George J.

doi:10.1016/j.stemcr.2020.07.003

Cited by 15 publications

(9 citation statements)

References 72 publications

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“…For example, chronic activation of PERK is implicated in the neurodegeneration associated with amyloid diseases including AD and the prionoses (Bell et al, 2016;Hughes and Mallucci, 2019). The endogenous expression of disease-associated, amyloidogenic TTR variants in induced pluripotent stem cell-derived hepatocytes increase expression of ATF6 and XBP1s target genes, suggesting an important role for UPR-dependent regulation of secretory proteostasis in TTR amyloid disease (Giadone et al, 2020). Similar results were observed in cells expressing amyloidogenic variants of lysozyme (Kamada et al, 2015).…”

Section: Imbalanced Upr Signaling In Amyloid Disease Pathogenesismentioning

confidence: 60%

Stress-responsive regulation of extracellular proteostasis

Mesgarzadeh

Buxbaum

Wiseman

2022

Journal of Cell Biology

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Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous diseases. This has led to considerable interest in understanding the molecular mechanisms responsible for regulating proteostasis in extracellular environments such as the blood and cerebrospinal fluid (CSF). Extracellular proteostasis is largely dictated by biological pathways comprising chaperones, folding enzymes, and degradation factors localized to the ER and extracellular space. These pathways limit the accumulation of nonnative, potentially aggregation-prone proteins in extracellular environments. Many reviews discuss the molecular mechanisms by which these pathways impact the conformational integrity of the secreted proteome. Here, we instead focus on describing the stress-responsive mechanisms responsible for adapting ER and extracellular proteostasis pathways to protect the secreted proteome from pathologic insults that challenge these environments. Further, we highlight new strategies to identify stress-responsive pathways involved in regulating extracellular proteostasis and describe the pathologic and therapeutic implications for these pathways in human disease.

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Section: Imbalanced Upr Signaling In Amyloid Disease Pathogenesismentioning

confidence: 60%

Stress-responsive regulation of extracellular proteostasis

Mesgarzadeh

Buxbaum

Wiseman

2022

Journal of Cell Biology

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“…As our group and others have identified differential regulation of ER stress machinery in cells producing and interacting with pathology-associated TTRs and LCs 10,11 , we sought to compare these responses to changes elicited by HS and thapsigargin. In doing so, we generated transcriptional and chromatin accessibility profiles of neuronal SH-SY5Y and cardiac AC16 cells undergoing HS and global UPR activation via thapsigargin.…”

Section: Discussionmentioning

confidence: 99%

“…Cells respond to a variety of stimuli including xenobiotic, oxidative, and ER stress through complex intracellular signaling pathways 14,15,19,20 . Activation of these pathways can result in reprogramming of transcriptional networks in an effort to maintain function during acute stress, disease, and aging 1,9,10 . As many stress response pathways share downstream convergent mechanisms (e.g.…”

Section: Introductionmentioning

confidence: 99%

Mapping Cellular Response to Destabilized Transthyretin Reveals Cell- and Amyloidogenic Protein-Specific Signatures

Ghosh

Villacorta‐Martin

Lindstrom-Vautrin

et al. 2022

Preprint

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In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive. In an effort to define early events of TTR-associated stress, we exposed neuronal (SH-SY5Y) and cardiac (AC16) cells to wild-type and destabilized TTR variants (TTRV122I and TTRL55P) and performed transcriptional (RNAseq) and epigenetic (ATACseq) profiling. We subsequently compared TTR-responsive signatures to cells exposed to destabilized antibody light chain protein associated with AL amyloidosis as well as ER stressors (thapsigargin, heat shock). In doing so, we observed overlapping, yet distinct cell type- and amyloidogenic protein-specific signatures, suggesting unique responses to each amyloidogenic variant. Moreover, we identified chromatin level changes in AC16 cells exposed to mutant TTR which resolved upon pre-incubation with kinetic stabilizer tafamidis. Collectively, these data provide insight into the mechanisms underlying amyloid-mediated cellular damage and provide a robust resource representing cellular responses to aggregation-prone proteins and ER stress.

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“…[9][10][11][12] Transcriptomic profiling can help further characterize pathological insults and improve biomarker discovery by allowing for the rapid and simultaneous measurement of thousands of variables associated with disease states. [26,27] However, applying laboratory-based indicators of cardiac dysfunction for clinical use is more complex.…”

Section: Introductionmentioning

confidence: 99%

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

Edwards,

Ferri,

Villegas-Galaviz

et al. 2024

Preprint

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Background: Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity are not well understood. We identified gene expression changes correlating with human cardiac cells exposed to a cardiomyopathy-associated κAL LC. We then sought to confirm these findings in a clinical dataset by focusing on clinical parameters associated with the pathways dysregulated at the gene expression level. Upon exposure to a cardiomyopathy-associated κAL LC, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in GLS on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal IVSd but abnormal cardiac biomarkers suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.

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Expression of Amyloidogenic Transthyretin Drives Hepatic Proteostasis Remodeling in an Induced Pluripotent Stem Cell Model of Systemic Amyloid Disease

Cited by 15 publications

References 72 publications

Stress-responsive regulation of extracellular proteostasis

Stress-responsive regulation of extracellular proteostasis

Mapping Cellular Response to Destabilized Transthyretin Reveals Cell- and Amyloidogenic Protein-Specific Signatures

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

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