Researchers have developed an innovative approach to generate antibodies that target protein aggregates, offering a promising tool to study the toxic clumping of proteins associated with neurodegenerative diseases like Alzheimer’s and Parkinson’s. The breakthrough, which will be presented at the 69th Biophysical Society Annual Meeting in Los Angeles this week, addresses significant challenges in studying the complex and transient structures of these aggregates.
Proteins such as amyloid-beta and alpha-synuclein misfold and clump together, forming oligomers that are toxic to brain cells. However, these aggregates are difficult to study with traditional techniques due to their fleeting nature and structural variability. While antibodies are effective in binding specific targets, creating antibodies for these transient aggregates has been a major hurdle in the field.
A team led by Dr. Francesco Aprile, Associate Professor of Biological Chemistry at Imperial College London, has developed a platform that combines computational design and directed evolution to generate antibodies capable of binding to and inhibiting the aggregation process. This advancement significantly speeds up the discovery and production of antibodies, saving valuable time and resources.
The team’s method led to the creation of single-domain antibodies, or nanobodies, that target intrinsically disordered proteins—proteins that lack a fixed three-dimensional structure and fluctuate constantly. These proteins, including amyloid-beta and alpha-synuclein, are known to self-assemble into harmful oligomers, which are characteristic of diseases like Alzheimer’s and Parkinson’s.
The nanobodies generated in this study target these protein assemblies and provide new insights into the mechanisms that drive the formation of toxic aggregates. “By efficiently generating nanobodies against these challenging targets, we can now explore the underlying processes of protein self-assembly and its role in disease,” said Dr. Aprile.
The research has also pinpointed specific regions within amyloid-beta and alpha-synuclein that could serve as potential therapeutic targets. This discovery opens up new possibilities for developing drugs that could slow or even prevent the progression of these debilitating diseases.
As Dr. Aprile emphasized, “By targeting these key protein assemblies, we may be able to slow or even prevent disease progression, offering hope for more effective treatments in the future.”
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