Transthyretin (TTR) is one of the major amyloidogenic proteins in systemic amyloidosis. It forms extracellular amyloid deposits in systemic organs like nerves, ligaments, heart, and arterioles, causing two types of systemic amyloidosis: hereditary ATTR (ATTRv) amyloidosis induced by variant TTR and aging-related wild-type ATTR (ATTRwt) amyloidosis [1]. TTR is also involved in maintaining cellular proteostasis, as it can respond to excessive TARDBP (associated with neurological disorders) by promoting autophagy and facilitating the degradation of aggregated TARDBP [3].

Mutations in the TTR gene are associated with Familial amyloidotic polyneuropathy (FAP). Transgenic mouse models, such as the TTR exon-humanized mouse, have been developed to study FAP. These models help in understanding the disease mechanism and testing new therapies [2]. In the HSF ± hTTR V30M mouse model, which expresses human TTRV30M in a Ttr null background, studies on TTR deposition in the heart have provided insights into the cellular environment of TTR deposits in ATTR-Cardiomyopathy, potentially leading to new therapeutic strategies [4].

In conclusion, TTR is crucial in the context of systemic amyloidosis and neurological disorders. Mouse models, especially those with modified TTR genes, have significantly contributed to understanding the role of TTR in diseases like FAP and ATTR-Cardiomyopathy, enabling the development of new treatment strategies for these conditions.

References:

1. Ueda, Mitsuharu. 2022. Transthyretin: Its function and amyloid formation. In Neurochemistry international, 155, 105313. doi:10.1016/j.neuint.2022.105313. https://pubmed.ncbi.nlm.nih.gov/35218869/

2. Li, Zhenghua, Kanazashi, Hideki, Tokashiki, Yoshimi, Chen, Hong, Yamamura, Kenichi. 2022. TTR exon-humanized mouse optimal for verifying new therapies for FAP. In Biochemical and biophysical research communications, 599, 69-74. doi:10.1016/j.bbrc.2022.02.035. https://pubmed.ncbi.nlm.nih.gov/35176627/

3. Chu, Yuan-Ping, Ho, Pei-Chuan, Tsai, Kuen-Jer. 2023. TTR (transthyretin) leads the autophagy disaster relief team against TARDBP/TDP-43 proteinopathy. In Autophagy, 19, 2403-2405. doi:10.1080/15548627.2023.2167690. https://pubmed.ncbi.nlm.nih.gov/36633448/

4. Teixeira, Cristina, Martins, Helena Sofia, Saraiva, Maria João. 2023. Cellular environment of TTR deposits in an animal model of ATTR-Cardiomyopathy. In Frontiers in molecular biosciences, 10, 1144049. doi:10.3389/fmolb.2023.1144049. https://pubmed.ncbi.nlm.nih.gov/36968272/