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Dimeric transthyretin variant assembles into spherical neurotoxins
Kimiaki Matsubara1, Mineyuki Mizuguchi, Kouhei Igarashi
1Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.
Biochemistry
|March 2, 2005
Summary
Familial amyloidotic polyneuropathy is caused by transthyretin mutations. The Ser112Ile variant forms unstable dimers, spherical aggregates, and induces neuroblastoma cell death, highlighting a mechanism for this hereditary disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Familial amyloidotic polyneuropathy (FAP) is a hereditary, autosomal-dominant disorder.
- Transthyretin (TTR) amyloid fibrils are central to FAP pathogenesis.
- Amyloidogenic mutations in TTR lead to fibril deposition.
Purpose of the Study:
- To investigate the structure and stability of the human Ser112Ile TTR variant.
- To understand the aggregation pathway and cellular effects of this FAP-associated TTR variant.
Main Methods:
- Protein structural analysis of the Ser112Ile TTR variant.
- Cell-based assays using a human neuroblastoma cell line.
- Assessment of cytotoxicity induced by the TTR variant.
Main Results:
- The Ser112Ile TTR variant forms a dimer with nonnative tertiary structure at physiological pH.
- This dimeric form self-assembles into spherical aggregates.
- The spherical aggregates exhibit cytotoxicity in a human neuroblastoma cell line.
Conclusions:
- An unstable dimeric structure of TTR is crucial for the formation of cytotoxic spherical aggregates.
- These aggregates contribute to cell death, offering insight into FAP mechanisms.
- Targeting TTR dimer instability may present a therapeutic strategy for FAP.