Authors
James Joly, Vivekananda Budamagunta, Zhengjian Zhang, Brittany Nortman, Maryam Jouzi, Rajat Bhatnagar, Jarrett D Egertson, Michael E Flaster, Rob Grothe, Sanjib Guha, Kota Kaneshige, Kevin McVey, Nicholas Nelson, Rukshan T Perera, Steven J Tan, Tuan Trinh, David Arnott, Joanna Lipka, Nikhil J Pandya, Lionel Rougé, Timothy J Wendorff, Donald S Kirkpatrick, Alexis Rohou, David C Butler, Steven Lotz, Ana Forton, Emily R Sartori, Jessica E Schwarz, Phillip S Brereton, Kevin Chen, Michael A Darcy, Hamid R Golnabi, Ross Hartley, Pierre F Indermuhl, Christina E Inman, Kevin M Jin, Stanislav Katsyuk, Rajesh Kota, Bryant Lowry, Jonathan C Menger, Denise A Miller, Maureen R Newman, Adedeji Ogunyemi, Julia K Robinson, Noah Steiner, Juanfeng Sun, Scott M Tabakman, Lisen Wang, Zhiqiang Wang, Sheri K Wilcox, Nautilus Biotechnology, Gregory T Kapp, Sujal Patel, Sally Temple, Taylor Bertucci, Joel Blanchard, Andreas F R Huhmer, Subramanian V Sankar, Kara Juneau, Parag Mallick
Published in
Nature methods. Volume 23. Issue 9. Pages 1786-1797. Epub Sep 04, 2026.
Abstract
Proteins exist as diverse proteoforms resulting from a combination of genetic variation, alternative splicing and post-translational modifications. Current methods struggle to capture this complexity at the single-molecule level. Here we introduce Iterative Mapping of proteoforms, a method that enables massively parallel interrogation of millions to billions of single-protein molecules through iterative probing with fluorescently labeled antibodies. We applied Iterative Mapping to tau, a key protein in neurodegenerative diseases, using 12 site-specific antibodies. The tau proteoform assay demonstrates high sensitivity (detecting proteoforms at 0.1% abundance), high reproducibility (median coefficient of variation <5.5%) and broad dynamic range (>3 orders of magnitude), outperforming conventional techniques in resolving closely related proteoform groups. Analysis of relevant biological samples, including organoids, mouse brains and human Alzheimer's disease samples, revealed 130 distinct tau proteoform groups with as many as six phosphorylation events. The nonrandom distribution of these phosphorylation events suggests ordered and site-specific modification processes rather than random, stochastic accumulation. Iterative Mapping provides insights into proteoform complexity at the single-molecule level, with implications for understanding protein regulation in neurodegenerative diseases and beyond.
PMID:
42697987
Bibliographic data and abstract were imported from PubMed on 05 Sep 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 4
- Comments 0