Architecture of polyglutamine-containing fibrils from time-resolved fluorescence decay

Area of Science:

• Neurodegenerative diseases
• Protein misfolding and aggregation
• Structural biology

Background:

• Huntington disease (HD) and other repeat disorders are linked to expanded CAG repeats encoding polyglutamine (polyQ) tracts.
• PolyQ length dictates disease risk and onset, with misfolding and aggregation being key pathological features.
• The precise structure of polyQ aggregates in these diseases remains largely unknown.

Purpose of the Study:

• To determine the architecture of mature huntingtin (Htt) exon 1 fibrils in Huntington disease.
• To provide structural evidence for the polyQ length threshold observed in HD pathology.
• To establish a method for validating therapeutic interventions targeting amyloid formation.

Main Methods:

• Time-dependent fluorescent decay measurements on Htt exon 1 fibrils with expanded 51Q (Htt51Q).
• Utilizing structural models and varying fluorescent label positions to map distances within fibrils.
• Employing Monte Carlo simulations to test various monomer conformations against experimental data.

Main Results:

• The study identified two plausible structures for polyQ amyloid fibrils: a five-layered beta-sheet arrangement with alternating N-termini or a zipper-like layer with antiparallel stretches.
• These structures are consistent with the experimentally measured decay times and exclude other arrangements.
• The determined dimensions of the polyQ stretch support the existence of a length threshold for HD pathology.

Conclusions:

• The research elucidates the structural organization of polyQ amyloid fibrils in Huntington disease.
• The findings offer crucial insights into the molecular basis of polyQ repeat disorders.
• The developed methodology can assess the impact of drugs aimed at inhibiting or modifying amyloid formation and structure.