This post is an excerpt from our recently updated proteomics and neuroscience eBook. Download the full eBook here.
The last few decades have seen rapid advances in Alzheimer’s disease (AD) research. From the development of new brain imaging methods to novel biomarkers, to the approval of immunotherapies targeting proteins at the core of the disease, there’s much hope for breakthroughs that may prevent its devastating impacts. Along with these advances, researchers have realized that they need to understand much more about the proteins underlying the disease to more accurately stage patients and develop more effective treatments. Principal among these proteins is the microtubule-associated protein tau, which is known to aggregate in the brains of AD patients and is deeply associated with AD’s cognitive impacts. Researchers have made strides in targeting this and other AD-associated proteins, but all available treatments still only modestly slow and do not prevent cognitive decline. Gaining a deeper understanding of tau and its roles in not just AD, but many neurodegenerative diseases represents a critical path forward.
Toward this end, at Nautilus we’re proud that researchers are using the Nautilus Voyager™ Platform and its underlying Iterative Mapping methodology to explore AD and related dementias at an unprecedented level of depth. They’re deploying the Tau Proteoforms Assay to quantify tau variants or proteoforms (the versions of proteins found in biological systems) with single-molecule resolution and discovering how changes in the previously hidden proteoform landscape may be implicated in disease. In this edition of the Nautilus Biotechnology “Proteomics and neuroscience” eBook, we’re excited to:
- Dive into tau biology.
- Share what researchers are learning about tau and its role in AD using the Nautilus Voyager Platform.
- Invite you to use the Nautilus Voyager Platform in your own work through the Iterative Mapping Early Access Program – the first offering available through this program is the Tau Proteoforms Assay, and we’ll be adding new offerings soon.
Before we take a crash course on tau biology, first a little background on Iterative Mapping, our novel method for proteomic analysis underlying the Nautilus Voyager Platform. In it, billions of single protein molecules are immobilized on massive arrays, one protein molecule per optically distinguishable “landing pad”. Fluorescent probes that recognize specific protein or proteoform features are then applied in repeated cycles, and the binding pattern for every molecule is recorded. A machine learning algorithm converts those binding patterns into confident protein and proteoform identifications, which are simply counted for quantification with single-molecule accuracy, sensitivity, and reproducibility.
Critical to the work described here, Iterative Mapping is one of an exceedingly small number of methods capable of proteoform analysis. Proteoforms are the versions of canonical proteins actually found in biological systems. They likely drive much of biology and are defined by their unique combinations of sequence variations (due to alternative splicing for instance), post-translational modifications (PTMs), and any other sources of variation (Smith and Kelleher, 2013). Some traditional technologies can measure the abundance of isolated components of proteoforms – the abundances of isolated phosphosites for instance, but the Nautilus Voyager™ Platform is uniquely capable of determining which of these components come together on distinct proteoforms at scale. Given that it is the combination of PTMs and other variations found on proteins that determine their unique structures, functions, and ultimate impacts on biology, proteoform analysis may provide uniquely mechanistic insights into how cells and tissues adopt their functions and malfunction in health and disease.
As Iterative Mapping continues to be applied to challenges like those described herein, we believe it will revolutionize our understanding of biology. If you find yourself inspired by what you read and want to use the Nautilus Voyager Platform for your own targeted proteoform or broadscale proteomic analyses, please reach out.
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