Newly developed nanobody can penetrate tough brain cells and treat Parkinson's disease

Newly developed nanobody can penetrate tough brain cells and treat Parkinson's disease

Proteins called antibodies help the immune system find and attack foreign pathogens. Mini versions of antibodies called nanobodies -; natural compounds in the blood of animals such as llamas and sharks -; are being studied for the treatment of autoimmune diseases and cancer. Now researchers at Johns Hopkins Medicine have helped develop a nanobody capable of getting through the tough exterior of brain cells and untangling misshapen proteins that lead to Parkinson's disease, Lewy body dementia and other neurocognitive disorders caused by the harmful protein.

The study, published July 19 in Nature Communications, was a collaboration between researchers at Johns Hopkins Medicine led by Xiaobo Mao, Ph.D., and scientists at the University of Michigan, Ann Arbor. Their goal was to find a new type of treatment that could specifically target the misshapen proteins called alpha-synuclein, which tend to clump together and gum up the inner workings of brain cells. New evidence has shown that the alpha-synuclein clumps can spread from the gut or nose to the brain, driving disease progression.

In theory, antibodies have the potential to focus on clumping alpha-synuclein proteins, but the pathogen-fighting compounds have a hard time penetrating the outer shell of brain cells. To squeeze through tough coatings of brain cells, the researchers chose nanobodies, the smaller version of antibodies.

Traditionally, nanobodies created outside the cell cannot perform the same function inside the cell. So the researchers had to support the nanobodies so that they would remain stable in a brain cell. To do this, they genetically modified the nanobodies to free them from chemical bonds that are typically broken down within a cell. Tests showed that without the bonds, the nanobody remained stable and was still able to bind to misshapen alpha-synuclein.

The team made seven similar types of nanobodies, known as PFFNBs, that could bind to clumps of alpha-synuclein. Of the nanobodies they created, one is -; PFFNB2-; did the best work glomming clumps of alpha-synuclein rather than individual molecules or monomers of alpha-synuclein. Monomeric versions of alpha-synuclein are not harmful and may have important functions in brain cells. The researchers also needed to determine whether the PFFNB2 nanobody could remain stable and function in brain cells. The team found that PFFNB2 was stable in living mouse brain cells and tissue and showed strong affinity for clumps of alpha-synuclein rather than individual alpha-synuclein monomers.

Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from accumulating into clumps, but it can disrupt and destabilize the structure of existing clumps.

Remarkably, we induced PFFNB2 expression in the cortex and prevented alpha-synuclein clumps from spreading to the mouse brain cortex, the region responsible for cognition, movement, personality and other higher-order processes.”

Ramhari Kumbhar, Ph.D., co-first author, postdoctoral fellow, Johns Hopkins University School of Medicine

“PFFNB2's success in binding harmful alpha-synuclein clumps in increasingly complex environments suggests that the nanobody could be the key to helping scientists study these diseases and ultimately develop new treatments,” says Mao, associate professor of neurology.

Source:

Johns Hopkins Medicine