Seeding-dependent maturation of beta2-microglobulin amyloid fibrils at neutral pH

Area of Science:

• Biochemistry
• Molecular Biology
• Medical Research

Background:

• Dialysis-related amyloidosis involves beta2-microglobulin (beta2-m) amyloid fibrils.
• Reproducing amyloid fibril formation under physiological conditions is challenging.
• Previous work showed seed fibrils and low sodium dodecyl sulfate (SDS) enabled fibril formation at pH 7.0.

Purpose of the Study:

• To investigate the mechanism of beta2-m amyloid fibril formation and maturation at neutral pH.
• To understand how fibrils adapt to physiological conditions over time.
• To explore factors influencing fibril extension at neutral pH.

Main Methods:

• Utilized repeated self-seeding of pre-formed beta2-m fibrils at pH 7.0.
• Simulated fibril maturation using a model with two fibril types of differing growth rates.
• Investigated the effect of beta2-m mutations and urea on fibril extension.
• Assessed the necessity of low sodium dodecyl sulfate (SDS) concentration for fibril formation.

Main Results:

• Repeated self-seeding at pH 7.0 significantly accelerated fibril growth, indicating maturation.
• Fibril maturation could be modeled by assuming two fibril populations with distinct growth rates.
• Beta2-m mutations or urea alone did not promote fibril extension at pH 7.0.
• A low concentration of SDS (0.5 mM) was essential for fibril extension at neutral pH.

Conclusions:

• Beta2-m amyloid fibrils mature through repeated self-seeding at neutral pH.
• This maturation process allows initially unstable fibrils to adapt to physiological conditions.
• The findings suggest a mechanism for the long latent period observed in amyloid deposition diseases.