Nanobody Has Potential to Combat Alpha-synuclein Clumps

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A miniature antibody-like molecule called a nanobody effectively broke up toxic alpha-synuclein aggregates that are characteristic of Parkinson’s disease, and prevented the spread of these aggregates in the brains of mice in a disease model.

The novel construct was described in the journal Nature Communications, in the study, “[Alpha]-Synuclein fibril-specific nanobody reduces prion-like [alpha]-synuclein spreading in mice.”

“The success of PFFNB2 [the nanobody] 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,” Xiaobo Mao, PhD, a professor at Johns Hopkins University and co-author of the study, said in a press release.

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Antibodies are proteins made by the immune system that can bind to a single molecular target with extremely high specificity. Because they are so good at binding targets, antibodies have been used as a platform to develop treatments. One major limitation of these molecules, however, is that they are too large to easily pass into cells, and they are not very stable in the environment inside of cells.

Nanobodies, as the term suggests, are basically very small versions of antibodies — certain animals, such as sharks and llamas, make nanobodies instead of antibodies. Nanobodies are more stable inside of cells than antibodies.

“Nanobodies are preferred over conventional antibodies … for intracellular [within-cell] applications, as they are small, monomeric, stable, and commonly expressed inside cells,” the researchers wrote.

Scientists created a library of nanobodies designed to target aggregated alpha-synuclein, dubbed PFFNBs. After making some chemical modifications to increase the stability of these constructs, the researchers screened seven of them for their ability to bind to alpha-synuclein clumps.

Results showed that one of the nanobodies, dubbed PFFNB2, could effectively bind to clumped-up alpha-synuclein, but did not bind to single alpha-synuclein protein (monomers). The researchers noted that, since the alpha-synuclein protein normally is important for the function of nerve cells, targeting monomers might have unintended consequences on neuronal function.

In a battery of tests done using cells in dishes, the researchers showed that the PFFNB2 nanobody could not prevent alpha-synuclein monomers from forming clumps. But the nanobody was effective at breaking apart clumps once they formed.

The team next tested the nanobody in a mouse model of Parkinson’s. For these experiments, they used a specially engineered viral vector (AAV) to deliver genetic code with instructions for making PFFNB2 into the mouse’s brain cells. The cells then used the code to make the nanobody inside the cell.

Typically in Parkinson’s, alpha-synuclein aggregates spread in a “prion-like” manner, meaning aggregates in one brain region will prompt more aggregates to form in neighboring regions. Results showed the AAV-PFFNB2 treatment significantly reduced this toxic protein spread, with brain regions expressing the nanobody showing less alpha-synuclein aggregation.

“We believe this work provides a proof-of-concept that targets intracellular [alpha-synuclein] aggregates using AAV transduced [alpha-synuclein]-fibril-specific nanobody can effectively reduce” toxic protein spread, the researchers concluded.

The team noted that more research is ongoing to evaluate whether PFFNB2 also is effective outside of cells, improve its ability to get into the brain, and find more cost-effective methods for production.

“With further investigation and development, PFFNB2 holds therapeutic promise for treating” Parkinson’s and other disorders related to alpha-synuclein, the researchers concluded.

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