Neurology: Untangling a Culprit in Parkinson’s

Published in Hopkins Medicine - Fall 2022

Researchers at Johns Hopkins 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.

The team — involving a collaboration between Johns Hopkins Medicine researchers and scientists at the University of Michigan, and led by Johns Hopkins neuroscientist Xiaobo Mao — aimed 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. Emerging 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 potential for zeroing in on clumping alpha-synuclein proteins. But the pathogen-fighting compounds have a hard time getting through the outer covering of brain cells. To squeeze through tough brain cell coatings, the researchers decided to use the smaller version of antibodies, called nanobodies, which are natural compounds in the blood of animals such as llamas and sharks.

The team made seven similar types of nanobodies, known as PFFNBs, that could bind to alpha-synuclein clumps. Of the nanobodies they created, one — PFFNB2 — did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomer of alpha-synuclein. That’s important, since monomer versions of alpha-synuclein are not harmful and may have important functions in brain cells.

The researchers also needed to determine if the PFFNB2 nanobody could remain stable and work inside brain cells. The team found that in live mouse-brain cells and tissue, PFFNB2 was stable and showed a strong affinity to alpha-synuclein clumps rather than single alpha-synuclein monomers. Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from collecting into clumps, but it can disrupt and destabilize the structure of existing clumps.

“Strikingly, we induced PFFNB2 expression in the cortex, and it prevented alpha-synuclein clumps from spreading to the mouse brain’s cortex, the region responsible for cognition, movement, personality and other high-order processes,” says Johns Hopkins postdoctoral fellow Ramhari Kumbhar, co-first author of the study, which appeared in Nature Communications.

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