Dataset Information

Extracellular Vesicles Contribute to the Metabolism of Transthyretin Amyloid in Hereditary Transthyretin Amyloidosis.

ABSTRACT: Hereditary (variant) transthyretin amyloidosis (ATTRv amyloidosis), which is caused by variants in the transthyretin (TTR) gene, leads to TTR amyloid deposits in multiple organs and various symptoms such as limb ataxia, muscle weakness, and cardiac failure. Interaction between amyloid proteins and extracellular vesicles (EVs), which are secreted by various cells, is known to promote the clearance of the proteins, but it is unclear whether EVs are involved in the formation and deposition of TTR amyloid in ATTRv amyloidosis. To clarify the relationship between ATTRv amyloidosis and EVs, serum-derived EVs were analyzed. In this study, we showed that cell-derived EVs are involved in the formation of TTR amyloid deposits on the membrane of small EVs, as well as the deposition of TTR amyloid in cells. Human serum-derived small EVs also altered the degree of aggregation and deposition of TTR. Furthermore, the amount of TTR aggregates in serum-derived small EVs in patients with ATTRv amyloidosis was lower than that in healthy controls. These results indicate that EVs contribute to the metabolism of TTR amyloid, and suggest that TTR in serum-derived small EVs is a potential target for future ATTRv amyloidosis diagnosis and therapy.

SUBMITTER: Yamaguchi H

PROVIDER: S-EPMC8983912 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Extracellular Vesicles Contribute to the Metabolism of Transthyretin Amyloid in Hereditary Transthyretin Amyloidosis.

Yamaguchi Hiroki H Kawahara Hironori H Kodera Noriyuki N Kumaki Ayanori A Tada Yasutake Y Tang Zixin Z Sakai Kenji K Ono Kenjiro K Yamada Masahito M Hanayama Rikinari R

Frontiers in molecular biosciences 20220323

Hereditary (variant) transthyretin amyloidosis (ATTRv amyloidosis), which is caused by variants in the transthyretin (TTR) gene, leads to TTR amyloid deposits in multiple organs and various symptoms such as limb ataxia, muscle weakness, and cardiac failure. Interaction between amyloid proteins and extracellular vesicles (EVs), which are secreted by various cells, is known to promote the clearance of the proteins, but it is unclear whether EVs are involved in the formation and deposition of TTR a ...[more]

PMID: 35402512

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Project description:PurposeTransthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.Material and methodsEchocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.ResultsThere was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.ConclusionThis study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

Project description:BACKGROUND:Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. OBJECTIVES:The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. METHODS:Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189). RESULTS:U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival. CONCLUSIONS:In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

Dataset Information

Extracellular Vesicles Contribute to the Metabolism of Transthyretin Amyloid in Hereditary Transthyretin Amyloidosis.

Publications

Extracellular Vesicles Contribute to the Metabolism of Transthyretin Amyloid in Hereditary Transthyretin Amyloidosis.

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