Researchers say a new antibody discovery platform can delve deeper into the mechanisms underlying the processes behind Alzheimer’s and Parkinson’s diseases.
In diseases like Parkinson’s and Alzheimer’s, specific proteins misfold and clump together, forming toxic aggregates that damage brain cells.
The process of proteins spontaneously clumping is called protein aggregation. Researchers have now developed novel methods to generate aggregate-specific antibodies as specific probes or modulators of the aggregation process.
This new method overcomes significant challenges in characterizing these complex and often transient protein structures.
Antibodies, known for their precise target binding, offer a powerful tool for investigating these structures, but generating antibodies against such transitory targets has been a major hurdle.
This new platform integrates computational design and directed evolution to develop new antibodies, which are then screened for their ability to bind to target aggregates or inhibit the aggregation process.
“We can substantially speed up the process of discovery and production, which can save time and resources,” said Francesco Aprile, PhD, Associate Professor in Biological Chemistry at Imperial College London, who led the study.
Using this platform, Aprile and colleagues successfully generated single-domain antibodies (nanobodies) targeting intrinsically disordered proteins, or proteins that are not defined by one specific three-dimensional structure, but that are constantly changing.
“What these intrinsically disordered proteins do is they start to self-assemble and form oligomers and aggregates such as amyloid fibrils, which are a hallmark of Alzheimer’s,” Aprile noted.
The nanobodies the researchers developed can target different assemblies of amyloid-beta and alpha-synuclein, proteins associated with Alzheimer’s and Parkinson’s diseases, respectively.
These nanobodies can provide valuable insights into what makes these proteins form toxic oligomers.
“Our platform represents a significant advance in our ability to study protein self-assembly,” said Aprile. “By efficiently generating nanobodies against these challenging targets, we can now delve deeper into the mechanisms underlying these processes and their role in disease.”
Importantly, the research has identified specific regions within amyloid-beta and alpha-synuclein that could be promising therapeutic targets. This discovery opens new avenues for drug development aimed at treating Alzheimer’s and Parkinson’s.
By targeting these key protein assemblies, we may be able to slow or even prevent disease progression, said Aprile.
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