Amyloid-motif-dependent tau self-assembly is modulated by isoform sequence context.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Microtubule-associated protein tau (tau) is central to neurodegenerative diseases, particularly those involving amyloid formation.
• Mutations in tau linked to frontotemporal dementia enhance its aggregation and impair microtubule binding.
• The precise structural link between tau's aggregation propensity and its biological activity is not fully understood.

Purpose of the Study:

• To investigate the structural relationship between tau aggregation and biological activity.
• To engineer tau sequences that modulate its structural ensemble, reducing aggregation while preserving function.
• To understand the differential pathogenesis of tau isoforms (3R vs. 4R).

Main Methods:

• Multi-disciplinary approach combining computational modeling, Nuclear Magnetic Resonance (NMR), and cross-linking mass spectrometry.
• Engineering of tau sequences focusing on the conserved "PGGG" β-turn motif.
• Utilizing cell models to assess the impact of engineered tau on aggregation and microtubule binding.

Main Results:

• Specific substitutions near the "PGGG" motif, guided by tau isoform context, effectively reduced tau aggregation in vitro.
• Engineered tau sequences counteracted aggregation caused by disease-associated mutations.
• The engineered tau maintained essential microtubule-binding activity.
• Findings provide a structural basis for the reduced pathogenicity of 3R tau isoforms compared to 4R.

Conclusions:

• A mechanism for reducing pathogenic tau species formation while preserving biological function has been proposed.
• Engineered tau offers potential therapeutic avenues for neurodegenerative diseases characterized by tau misfolding.
• Understanding tau structure-function relationships is key to developing targeted treatments.