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Researchers have engineered a nanobody that can penetrate through the tough exterior of mouse brain cells and cleave the malformed proteins that lead to Parkinson’s disease, Lewy body dementia and other neurocognitive disorders.
Proteins, called antibodies, help the immune system find and attack foreign pathogens. Scientists are studying smaller versions of antibodies called nanobodies — compounds naturally found in the blood of animals like llamas and sharks — to treat autoimmune diseases and cancer.
New research published in nature communicationThe study is a collaboration between researchers at Johns Hopkins Medicine led by Xiaobo Mao and scientists at the University of Michigan, Ann Arbor.
They wanted to find a new type of treatment that could specifically target malformed proteins called alpha-synuclein, which clump together and glue the inner workings of brain cells. New evidence suggests that alpha-synuclein clusters can spread from the gut or nose to the brain, leading to disease progression.
In theory, antibodies have the ability to target the clumping of alpha-synuclein proteins, but compounds that fight pathogens have a harder time penetrating the outer covering of brain cells. To squeeze through tough coatings of brain cells, the researchers turned to nanobodies, the smaller version of the antibody.
Traditionally, nanobodies created outside the cell cannot perform the same function inside the cell. Therefore, the researchers had to support the nanobodies to keep them stable in the brain cell. To do this, they genetically engineered the nanobodies to eliminate the chemical bonds that normally break down in a cell. Tests showed that, without binding, none remained stable and still able to bind to missense alpha synuclein.
The team created seven similar types of nanobodies, known as PFFNBs, that can bind to clumps of alpha-synuclein. Of the nanobodies they made, one – PFFNB2 – did the best job of glowing clumps of alpha-synuclein, but not individual molecules or monomers of alpha-synuclein. The monomeric versions of alpha-synuclein are not harmful and can perform important functions in brain cells. Researchers also needed to determine whether PFFNB2 nanoparticles could remain stable and function in brain cells. The team found that PFFNB2 was stable in live mouse brain cells and tissues and showed a strong affinity for clumps of alpha-synuclein rather than individual alpha-synuclein monomers.
Additional tests in mice showed that PFFNB2-Nanonone could not prevent alpha-synuclein aggregation into clumps, but could disrupt and destabilize the structure of existing clumps.
“Surprisingly, we induced PFFNB2 expression in the cortex, and this prevented clumps of alpha-synuclein from spreading to the mouse brain cortex, the region responsible for cognition, movement, personality and other higher-order processes,” Ramhari said . Kumbhar, co-first author of the work and a postdoctoral fellow at Johns Hopkins University School of Medicine.
“The success of PFFNB2 in binding to harmful clumps of alpha-synuclein in an increasingly complex environment shows that everything important may be needed to help scientists study these diseases and eventually develop new treatments,” says Mao, associate Professor of Neurology. could.”
Additional collaborators are from the Johns Hopkins University School of Medicine; University of Michigan, Ann Arbor; and Tsinghua University.
Support for the work came from the University of Michigan, the National Institutes of Health, the Parkinson’s Foundation, and the Maryland Stem Cell Research Foundation’s Discovery Award.
Source: Johns Hopkins University