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Into the (Mis)fold: a Diagnostic Tool for Proteins

Molecular Foundry user Cleo Salisbury, a scientist at Novartis Diagnostics (left) and Ron Zuckermann, Director of the Biological Nanostructures Facility at the Molecular Foundry, discuss a technique for detecting misfolded proteins.Now, scientists at Berkeley Lab have engineered a universal, highly sensitive technique for detecting misfolded proteins in biological fluids. This groundbreaking nanoscience capability could help pinpoint Alzheimer’s in its early stages and enable researchers to discover new therapies for this devastating disease. (Credit: Berkeley Lab)


Alzheimer’s disease is the most common form of dementia, currently affecting more than 35 million people worldwide. Although many genetic and hereditary factors are thought to contribute to the telltale deterioration of memory and cognitive functions resulting from Alzheimer’s, a central aspect to this disease is an accumulation of misfolded proteins in the brain.

When a protein doesn’t fold into its normal shape, it also doesn’t perform its normal functions. This disruption in behavior could lead to proteins that aggregate into plaques or deposits and become toxic to cells. In Alzheimer’s disease, aggregates of a protein called beta-amyloid form in the central nervous system, causing damage to cells in the brain and triggering dementia.

An analytical capability for measuring tiny clusters of these proteins—before irreversible damage occurs—would be a powerful tool in the early detection of Alzheimer’s and other misfolded protein diseases. However, despite significant research efforts, there are currently no diagnostic tools available to selectively detect small-scale aggregates of misfolded proteins in biological fluids, such as blood or spinal fluid.

“This collaboration illustrates how a biomedical problem can also be a nanoscience problem, in which a chemical reagent is needed to recognize partially aggregated proteins,” said Ron Zuckermann, Director of the Biological Nanostructures Facility at the Molecular Foundry, a nanoscience user facility at Berkeley Lab. “We were faced with the challenge of synthesizing a material that’s capable of specifically detecting this aggregated protein and not any of the other proteins in the blood.”

Zuckermann is a pioneer in the development of peptoids, synthetic polymers that behave like naturally occurring proteins but can withstand aggressive chemical and biological environments without degrading. His group previously discovered peptoids capable of self-assembling into nanoscale jaws, nanosheets, and nanoscale ropes that braid themselves.

“Peptoids are ideal for this application as they are similar to proteins in structure, but different enough that they aren’t degraded by enzymes in the blood,” added Zuckermann. “We can now engineer materials that are capable of specific recognition yet can evade destruction.”

Using the Foundry’s state-of-the-art robotic synthesis capabilities, the team prepared a panel of peptoids designed to capture a misfolded prion protein, an abnormal, infectious form of a cellular protein found in the brain. By attaching these peptoids to tiny magnetic beads, the team could then use a magnet to isolate misfolded proteins directly from blood samples. The most selective and sensitive of these peptoids, coined aggregate-specific reagent, or ASR1, could capture not only the prion aggregates, but aggregates associated with Alzheimer’s disease as well.

“Our study shows how basic research capabilities can be translated into a practical application,” said Zuckermann. “The potential for this tool to serve as a diagnostic in other misfolded protein diseases, such as Parkinson’s and Type II diabetes, is wide open, and I’m excited to continue this collaboration.”

This research is reported in a paper titled, “A universal method for detection of amyloidogenic misfolded proteins,” appearing in the journal Biochemistry and available in Biochemistry online. Co-authoring the paper with Zuckermann were Cleo Salisbury, Xuemei Wang, Carol Gao, Michael Connolly, Thieu Bleu, John Hall, Joseph Fedynyshyn, Sophie Allauzen and David Peretz.

Portions of this work were supported by DOE’s Office of Science.

The Molecular Foundry is one of the five DOE Nanoscale Science Research Centers (NSRCs), premier national user facilities for interdisciplinary research at the nanoscale.  Together the NSRCs comprise a suite of complementary facilities that provide researchers with state-of-the-art capabilities to fabricate, process, characterize and model nanoscale materials, and constitute the largest infrastructure investment of the National Nanotechnology Initiative.  The NSRCs are located at DOE’s Argonne, Brookhaven, Lawrence Berkeley, Oak Ridge and Sandia and Los Alamos National Laboratories.  For more information about the DOE NSRCs, please visit

Lawrence Berkeley National Laboratory addresses the world’s most urgent scientific challenges by advancing sustainable energy, protecting human health, creating new materials, and revealing the origin and fate of the universe. Founded in 1931, Berkeley Lab’s scientific expertise has been recognized with 12 Nobel prizes. The University of California manages Berkeley Lab for the U.S. Department of Energy’s Office of Science. For more, visit