Abstracts are provided in the language submitted.

Introduction: Transthyretin amyloidosis (ATTR) is a progressive life-threatening disease characterized by the deposition of transthyretin (TTR) amyloid fibrils in the body’s organs and tissues, causing familial amyloid polyneuropathy (ATTR-FAP), cardiomyopathy (ATTR-FAC), or oculoleptomeningeal amyloidosis (OLMA). Several pathogenic variants have been shown to destabilize TTR tetramers, leading to aggregation of misfolded TTR fibrils. However, factors that underlie the differential age of disease onset amongst amyloidogenic TTR variants remain elusive. Materials and Methods: To understand these phenotypic differences, we generated TTR mutants with different disease onsets and study their amyloidogenic properties in cultured cells and Drosophila melanogaster. Results: We found similar cellular secretory pattern in both HEK and HepG2 cells for wild-type (WT) TTR to those of the late-onset mutant (Ala97Ser), stable mutant (Thr119Met), early-onset mutant (Val30Met), but not unstable mutant (Asp18Gly). Cytotoxicity assays revealed their toxicities in the order of Val30Met>Ala97Ser>WT>Thr119Met in IMR-32 neuroblastoma cells. Surprisingly, while early onset amyloidogenic TTR monomers are retained by the endoplasmic reticulum quality control (ERQC), late-onset amyloidogenic TTR monomers can be secreted extracellularly. Interestingly, Ala97Ser TTR overexpression in Drosophila causes late-onset neurodegeneration but aggressively shortened lifespan, recapitulating human disease progression. Conclusion: Our study demonstrates that escape of TTR monomers from the ERQC may underlie late-onset amyloidogenesis in patients and suggests potential treatment strategies targeting ERQC for mitigating late-onset ATTR.

Dr. Ridwan Ibrahim