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

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• The microtubule-associated protein tau is central to neurodegenerative diseases, with mutations linked to frontotemporal dementia increasing its aggregation.
• The relationship between tau's aggregation propensity and its biological function, particularly microtubule binding, is not fully understood.
• Understanding this relationship is crucial for developing targeted therapies.

Purpose of the Study:

• To engineer tau protein sequences that modulate its structural ensemble, reducing aggregation propensity while preserving biological activity.
• To investigate the structural underpinnings of tau aggregation and its link to disease-associated mutations.
• To explore therapeutic strategies for neurodegenerative diseases by targeting tau misfolding.

Main Methods:

• Utilized a multi-disciplinary approach combining computational modeling, Nuclear Magnetic Resonance (NMR) spectroscopy, and cross-linking mass spectrometry.
• Employed cell models to assess the in vitro and cellular effects of engineered tau sequences.
• Focused on substitutions near the conserved 'PGGG' β-turn motif, considering tau isoform context.

Main Results:

• Engineered tau sequences demonstrated reduced aggregation in vitro and in cellular models.
• Specific substitutions counteracted aggregation induced by disease-associated proline-to-serine mutations.
• Engineered tau variants maintained essential microtubule-binding activity.
• Findings provide a mechanistic explanation for the differential pathogenesis of tau isoforms (3R vs. 4R).

Conclusions:

• A strategy exists to reduce pathogenic tau species formation while preserving biological function.
• Targeting the 'PGGG' motif offers a potential therapeutic avenue for neurodegenerative diseases.
• This work provides insights into tau protein misfolding and its implications for disease pathogenesis.