Modified nanobodies clear protein clumps associated with Parkinson’s disease

August 2, 2022
Modified nanobodies clear protein clumps associated with Parkinson’s disease

Neurodegenerative diseases such as Parkinson’s disease are caused by protein aggregations that disrupt the normal functioning of neurons in the brain. Researchers at Johns Hopkins Medicine and the University of Michigan have created a type of antibody that acts upon and unravels the protein clumps, known as Lewy bodies. The antibody’ success in targeting the problematic clumps lends hope to developing new treatments especially for neurodegenerative conditions.

In order to break apart the clumps, researchers had genetically modified nanobodies, which are smaller versions of antibody proteins, to squeeze through the membranes of brain cells, and bind to and break down the clumps of misshapen proteins, alpha-synuclein.

Normally, these nanobodies would break down inside the cells because of degrading chemical bonds within their structure. But, when the researchers engineered the nanobodies to lack these certain bonds, they found that the nanobodies remained stable without reducing their ability to bind to alpha-synuclein clumps.

After testing seven versions of the modified nanobodies, the researchers identified one, called PFFNB2, as the best candidate. In tests in live brain cells and tissue of mice, PFFNB2 was found to strongly bind and effectively break down alpha-synuclein clumps.

“We induced PFFNB2 expression in the cortex [where] 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,” said Ramhari Kumbhar, postdoctoral fellow at the Johns Hopkins University School of Medicine.

Additional tests in mice revealed that PFFNB2 only acted on existing alpha-synuclein clumps and was unable to prevent them from forming into clumps in the first place. Most importantly, PFFNB2 worked around the individual molecules that are vital to brain function.

“The success of PFFNB2 in binding harmful alpha-synuclein clumps in increasingly complex environments indicates that the nanobody could be key to helping scientists study these diseases and eventually develop new treatments” said Xiaobo Mao, Associate Professor of Medicine at Johns Hopkins University School of Medicine.


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