Local structural preferences in shaping tau amyloid polymorphism

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tauopathies are neurodegenerative diseases defined by varied tau amyloid fibril structures.
• The underlying reasons for tau polymorphism across different diseases are not fully understood.
• Intrinsic structural properties of tau amyloid cores may influence fibril polymorphism.

Purpose of the Study:

• To identify intrinsic structural elements contributing to tau amyloid fibril polymorphism.
• To investigate the role of these elements in tau propagation within neurodegenerative diseases.

Main Methods:

• Experimental identification of a novel amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4).
• Computational analysis of per-residue contributions to fibril core stability.
• Cryo-electron microscopy (cryo-EM) of synthetic PAM4 peptide fibrils.
• In-cell experiments assessing the seeding efficiency of tau aggregates with and without PAM4.

Main Results:

• A new motif, PAM4, was identified as a significant contributor to tau polymorphism.
• PAM4 plays a key role in maintaining structural integrity across different amyloid polymorphs.
• Synthetic PAM4 peptides formed structures mimicking disease-associated tau strains.
• Deletion of PAM4 reduced the cellular seeding efficiency of tau aggregates from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.

Conclusions:

• Intrinsic structural propensities of amyloid core segments, like PAM4, dictate tau structure in cells.
• PAM4 is pivotal in the propagation of tau amyloid structures in tauopathies.
• Understanding PAM4's role offers insights into the molecular mechanisms driving neurodegeneration.