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Published on: September 5, 2019
Co-precipitation molecules hemopexin and transferrin may be key molecules for fibrillogenesis in TTR V30M
Mika Ohta1, Aki Sugano1, Naoya Hatano2
1Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, 650-0017, Japan.
Abstract:
The disease model of familial amyloidotic polyneuropathy-7.2-hMet30 mice-manifests amyloid deposition that consists of a human amyloidogenic mutant transthyretin (TTR) (TTR V30M). Our previous study found amyloid deposits in 14 of 27 7.2-hMet30 mice at 21-24 months of age. In addition, non-fibrillar TTR deposits were found in amyloid-negative 7.2hMet30 mice. These results suggested that TTR amyloidogenesis required not only mutant TTR but also an additional factor (or factors) as an etiologic molecule. To determine the differences in serum proteome in amyloid-positive and amyloid-negative mice in the 7.2-hMet30 model, we used proteomic analyses and studied serum samples obtained from these mice. Hemopexin (HPX) and transferrin (Tf) were detected in the serum samples from amyloid-positive mice and were also found in amyloid deposits via immunohistochemistry, but serum samples from amyloid-negative mice did not contain HPX and Tf. These two proteins were also not detected in non-fibrillar TTR deposits. In addition, in silico analyses suggested that HPX and Tf facilitate destabilization of TTR secondary structures and misfolding of TTR. These results suggest that HPX and Tf may be associated with TTR amyloidogenesis after fibrillogenesis in vivo.
Insights
Familial amyloidotic polyneuropathy involves mutant transthyretin (TTR) amyloidogenesis. Researchers identified Hemopexin (HPX) and Transferrin (Tf) in amyloid-positive mice, suggesting they may promote TTR misfolding and disease progression.
Area of Science:
- Biochemistry
- Proteomics
- Neuroscience
Background:
- Familial amyloidotic polyneuropathy (FAP) is modeled using 7.2-hMet30 mice expressing mutant transthyretin (TTR V30M).
- Previous studies indicated TTR amyloidogenesis requires factors beyond the mutant TTR protein itself.
- Amyloid deposits and non-fibrillar TTR deposits were observed in different groups of these mice.
Purpose of the Study:
- To investigate differences in the serum proteome between amyloid-positive and amyloid-negative 7.2-hMet30 mice.
- To identify potential etiologic molecules contributing to TTR amyloidogenesis in FAP.
Main Methods:
- Proteomic analysis of serum samples from amyloid-positive and amyloid-negative 7.2-hMet30 mice.
- Immunohistochemistry to detect specific proteins within amyloid deposits.
- In silico analysis to predict protein interactions and effects on TTR structure.
Main Results:
- Hemopexin (HPX) and Transferrin (Tf) were detected in serum and amyloid deposits of amyloid-positive mice.
- HPX and Tf were absent in serum and non-fibrillar deposits of amyloid-negative mice.
- In silico analyses suggested HPX and Tf destabilize TTR secondary structure, promoting misfolding.
Conclusions:
- HPX and Tf are significantly associated with TTR amyloidogenesis in the 7.2-hMet30 mouse model.
- These proteins may play a crucial role in facilitating TTR misfolding and fibril formation in vivo.
- HPX and Tf represent potential therapeutic targets for FAP.
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