Flipping the switch: How cysteine oxidation directs tau amyloid conformations

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Tau protein misfolding and aggregation are hallmarks of human neurodegenerative diseases.
• Distinct fibril conformations of tau are observed in different diseases, suggesting varied pathological mechanisms.

Purpose of the Study:

• To investigate how specific structural modifications in tau can lead to distinct amyloid polymorphs.
• To explore the role of oxidative stress in directing tau polymorphism.

Main Methods:

• Utilized a specific tau isoform with four microtubule-binding repeats.
• Investigated the effect of intramolecular disulfide links between cysteine residues (cys291 and cys322).

Main Results:

• Identified that intramolecular disulfide links between cys291 and cys322 direct the formation of a structurally distinct amyloid polymorph.
• Demonstrated a specific mechanism by which tau polymorphism can be induced.

Conclusions:

• Oxidative stress can influence tau structure through disulfide bond formation.
• These findings provide insights into the molecular mechanisms underlying tau polymorphism in neurodegenerative conditions.