A Shared Amyloid Architecture in Cardiac Fibrils from Three Neuropathy-Associated ATTR Variants

Area of Science:

• Biochemistry
• Structural Biology
• Medical Genetics

Background:

• ATTR amyloidosis is systemic, caused by wild-type (ATTRwt) or mutant (ATTRv) transthyretin amyloid accumulation.
• Disease pathology and penetrance vary, with unclear links to amyloid structure.
• Neuropathy-associated variants like ATTRvI84S and ATTRv-V122Δ show polymorphic fibrils, unlike typical ATTR fibrils.

Purpose of the Study:

• To investigate the relationship between neuropathic symptoms, specific mutations, and amyloid structural diversity in ATTR amyloidosis.
• To elucidate the structural basis of variable clinical manifestations in ATTRv amyloidosis.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine ex-vivo fibril structures.
• Analysis of fibril structures from ATTRv-P24S, ATTRv-A25S, and ATTRv-D38A variants.

Main Results:

• Despite distinct mutations and diverse clinical phenotypes, the studied ATTRv variants share a common amyloid core.
• This shared core structure was previously identified in ATTRwt and cardiac ATTRv.

Conclusions:

• Structural consistency in the amyloid core exists across different ATTR variants and phenotypes.
• This finding supports the development of structure-guided diagnostic tools for the broad spectrum of ATTR amyloidosis.