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Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis
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Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers

Anvesh K R Dasari1, Robert M Hughes1, Sungsool Wi2

  • 1Department of Chemistry, East Carolina University, Greenville, NC, 27858, USA.

Scientific Reports
|January 12, 2019
PubMed

Insights

Researchers identified early-stage transthyretin (TTR) oligomers, revealing their partially folded structures and role in pathogenic aggregation. Understanding these cytotoxic intermediates is key to unraveling amyloid formation mechanisms.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Amyloid formation is linked to pathogenic aggregation processes.
  • Early-stage oligomers are critical for understanding these mechanisms.
  • Transthyretin (TTR) aggregation is implicated in various diseases.

Purpose of the Study:

  • To identify and characterize cytotoxic oligomeric intermediates during TTR aggregation.
  • To elucidate the structural properties of these early-stage TTR oligomers.
  • To compare the aggregation pathways of wild-type (WT) TTR and a G53A variant.

Main Methods:

  • Amyloid formation under specific conditions.
  • Structural analysis using circular dichroism (CD).
  • Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy.

Main Results:

  • TTR initially forms dimers, which assemble into hexamers, serving as building blocks for cytotoxic oligomers.
  • Wild-type TTR forms linear oligomers, while the G53A variant forms annular, pore-like oligomers.
  • Oligomers exhibit significant native-like beta-sheet structures (35-38%) but are more disordered (~60%) than native TTR; variant oligomers are less structured.

Conclusions:

  • Cytotoxic oligomers share partially folded structures, suggesting a common property.
  • The flexibility of TTR oligomers may offset entropic losses during aggregation.
  • Characterizing these intermediates provides insights into TTR-mediated amyloidosis.

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