Patient-specific induced pluripotent stem cells for understanding and assessing novel therapeutics for multisystem transthyretin amyloid disease

Giadone, Richard M.; Ghosh, Sabrina; Murphy, George J.

doi:10.1016/b978-0-12-823882-0.00011-4

Cited by 2 publications

(3 citation statements)

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“…The systemic amyloid diseases are a class of disorders in which effector organs produce proteins that misfold and aggregate, travel throughout circulation, and deposit extracellularly at distal target sites [1][2][3] . Two of the most prevalent examples of systemic amyloid diseases include transthyretin amyloidosis (ATTR amyloidosis) and light chain amyloidosis (AL amyloidosis).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the recent development of therapeutics for diseases like ATTR amyloidosis [1][2][3][4][5][6] , it remains unclear how deposition of extracellular, aggregated TTRs and LCs damage target cell types. At the same time, there is large diversity in the pathology of both ATTR and AL amyloidosis, with some patients exhibiting amyloid deposition and damage at peripheral nerves, while others develop significant cardiac disease [4][5][6] .…”

Section: Introductionmentioning

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%

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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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Section: Introductionmentioning

confidence: 99%