Large-scale single-molecule analysis of tau proteoforms.

Iterative Mapping reveals over 130 distinct tau proteoforms with up to six phosphorylation sites at the single-molecule level, surpassing traditional methods in sensitivity and resolution.

• Why it matters: Understanding the diversity and modification patterns of tau proteoforms is crucial for unraveling mechanisms underlying neurodegenerative diseases like Alzheimer's, yet current techniques lack the resolution to analyze this complexity comprehensively.
• What they did: The study developed Iterative Mapping, a high-throughput method using fluorescently labeled antibodies to probe millions to billions of individual tau molecules, identifying proteoform variations across biological samples.
• The result: This approach uncovered ordered, site-specific phosphorylation patterns, providing new insights into tau regulation and offering a powerful tool for studying protein modifications in disease contexts.