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Review
. 2025 Jul 1:16:1623185.
doi: 10.3389/fphys.2025.1623185. eCollection 2025.

Secretion of transthyretin: molecular mechanisms dependent on the endoplasmic reticulum

Jia Meng  1 , Shan-Jun Cai  1   2   3   4
Affiliations
Review

Secretion of transthyretin: molecular mechanisms dependent on the endoplasmic reticulum

Jia Meng et al. Front Physiol. .

Abstract

Hereditary transthyretin amyloidosis (ATTRv) results from genetic mutations that destabilize transthyretin (TTR), leading to the formation of extracellular aggregates and amyloid fibrils. A common pathological feature of ATTRv is the capacity of TTR variants to evade endoplasmic reticulum quality control (ERQC) and be secreted, underscoring the critical role of ER regulation in disease pathogenesis. Notably, the TTR Gly83Arg mutation causes familial vitreous amyloidosis, a subtype distinguished by abnormal TTR deposition in the ocular vitreous cavity. Current therapies for ATTRv are ineffective in crossing the blood-retinal barrier or in halting the progression of ocular amyloidosis. This review summarizes the molecular mechanisms of ER-regulated TTR secretion and explores potential causes of ocular amyloid deposition, aiming to provide mechanistic insights into familial vitreous amyloidosis.

Keywords: endoplasmic reticulum; endoplasmic reticulum quality control; transthyretin; unfolded protein response; vitreous amyloidosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of TTR secretion and extracellular aggregation.
FIGURE 2
FIGURE 2
Effect of UPR on TTR secretion.
FIGURE 3
FIGURE 3
Structure of TTR-RBP complex. (a) Structure representation of the TTR-RBP complex. TTR: blue. RBP4: pink. Retinol: green. (b) Detail of the contact at the residue level between TTR and RBP4.
See this image and copyright information in PMC

References

    1. Adams D., Sekijima Y., Conceição I., Waddington-Cruz M., Polydefkis M., Echaniz-Laguna A., et al. (2023). Hereditary transthyretin amyloid neuropathies: advances in pathophysiology, biomarkers, and treatment. Lancet Neurol. 22 (11), 1061–1074. 10.1016/S1474-4422(23)00334-4 - DOI - PubMed
    1. Adams D., Tournev I. L., Taylor M. S., Coelho T., Planté-Bordeneuve V., Berk J. L., et al. (2023). Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid 30 (1), 1–9. 10.1080/13506129.2022.2091985 - DOI - PubMed
    1. Almeida Mdo R., Lopez-Andreu F., Munar-Qués M., Costa P. P., Saraiva M. J. (1993). Transthyretin ALA 71: a new transthyretin variant in a Spanish family with familial amyloidotic polyneuropathy. Hum. Mutat. 2 (5), 420–421. 10.1002/humu.1380020516 - DOI - PubMed
    1. Ando Y., Adams D., Benson M. D., Berk J. L., Planté-Bordeneuve V., Coelho T., et al. (2022). Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid 29 (3), 143–155. 10.1080/13506129.2022.2052838 - DOI - PubMed
    1. Bishop P. N. (2000). Structural macromolecules and supramolecular organisation of the vitreous gel. Prog. Retin Eye Res. 19 (3), 323–344. 10.1016/s1350-9462(99)00016-6 - DOI - PubMed

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