標題: Cellular secretion and cytotoxicity of transthyretin mutant proteins underlie late-onset amyloidosis and neurodegeneration
作者: Ibrahim, Ridwan Babatunde
Yeh, Ssu-Yu
Lin, Kon-Ping
Ricardo, Frans
Yu, Tsyr-Yan
Chan, Chih-Chiang
Tsai, Jin-Wu
Liu, Yo-Tsen
生物科技學系
Department of Biological Science and Technology
關鍵字: Amyloidosis;Drosophila melanogaster;Endoplasmic reticulum quality control;ERQC;Proteostasis;Transthyretin;TTR
公開日期: 1-Apr-2020
摘要: Transthyretin amyloidosis (ATTR) is a progressive life-threatening disease characterized by the deposition of transthyretin (TTR) amyloid fibrils. 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. Here, we examined the biological properties of various TTR mutations and found that the cellular secretory pattern of the wild-type (WT) TTR was similar to those of the late-onset mutant (Ala97Ser, p. Ala117Ser), stable mutant (Thr119Met, p. Thr139Met), early-onset mutant (Val30Met, p. Val50Met), but not in the unstable mutant (Asp18Gly, p. Asp38Gly). Cytotoxicity assays revealed their toxicities in the order of Val30Met > Ala97Ser > WT > Thr119Met in neuroblastoma cells. Surprisingly, while early-onset amyloidogenic TTR monomers (M-TTRs) are retained by the endoplasmic reticulum quality control (ERQC), late-onset amyloidogenic M-TTRs can be secreted extracellularly. Treatment of thapsigargin (Tg) to activate the unfolded protein response (UPR) alleviates Ala97Ser M-TTR secretion. Interestingly, Ala97Ser TTR overexpression in Drosophila causes late-onset fast neurodegeneration and a relatively short lifespan, recapitulating human disease progression. Our study demonstrates that the escape of TTR monomers from the ERQC may underlie late-onset amyloidogenesis in patients and suggests that targeting ERQC could mitigate late-onset ATTR.
URI: http://dx.doi.org/10.1007/s00018-019-03357-1
http://hdl.handle.net/11536/154253
ISSN: 1420-682X
DOI: 10.1007/s00018-019-03357-1
期刊: CELLULAR AND MOLECULAR LIFE SCIENCES
Volume: 77
Issue: 7
起始頁: 1421
結束頁: 1434
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