Nanobody Penetrates Brain Cells to Halt the Progression of Parkinson’s

Researchers from the Johns Hopkins University School of 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. The research, published last month in Nature Communications, was led by Xiaobo Mao, an associate professor of neurology at the School of Medicine, and included scientists at the University of Michigan, Ann Arbor. Their aim 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. Emerging evidence has shown that the alpha-synuclein clumps can spread from the gut or nose to the brain, driving the disease progression.

Nanobodies—miniature versions of antibodies, which are proteins in the blood that help the immune system find and attack foreign pathogens—are natural compounds in the blood of animals such as llamas and sharks and are being studied to treat autoimmune diseases and cancer in humans. In theory, antibodies have the potential to zero in on clumping alpha-synuclein proteins, but have a hard time getting through the outer covering of brain cells. To squeeze through these tough brain cell coatings, the researchers decided to use nanobodies instead. The researchers had to shore up the nanobodies to help them keep stable within a brain cell. To do this, they genetically engineered them to rid them of chemical bonds that typically degrade inside 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 alpha-synuclein clumps. Of the nanobodies they created, onePFFNB2—did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomer of alpha-synuclein, which are not harmful and may have important functions in brain cells. 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.

The structure of alpha-synuclein clumps (left) was disrupted by the nanobody PFFNB2. The debris from the disrupted clump is shown on the right.

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 Ramhari Kumbhar, the co-first author and a postdoctoral fellow at the School of Medicine.

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,” Mao says.

Source: https://hub.jhu.edu/

Will Llamas Become Coronavirus Killers ?

Antibodies from Winter, a 4-year-old llama with great eyelashes, have neutralized coronavirus and other infections in lab experiments.

Winter is a 4-year-old chocolate-colored llama with spindly legs, ever-so-slightly askew ears and envy-inducing eyelashes. Some scientists hope she might be an important figure in the fight against the novel coronavirus.

She is not a superpowered camelid. Winter was simply the lucky llama chosen by researchers in Belgium, where she lives, to participate in a series of virus studies involving both SARS and MERS. Finding that her antibodies staved off those infections, the scientists posited that those same antibodies could also neutralize the new virus that causes Covid-19. They were right, and published their results in the journal Cell.

Scientists have long turned to llamas for antibody research. In the last decade, for example, scientists have used llamas’ antibodies in H.I.V. and influenza research, finding promising therapies for both viruses.

Humans produce only one kind of antibody, made of two types of protein chains heavy and light — that together form a Y shape. Heavy-chain proteins span the entire Y, while light-chain proteins touch only the Y’s arms. Llamas, on the other hand, produce two types of antibodies. One of those antibodies is similar in size and constitution to human antibodies. But the other is much smaller; it’s only about 25 percent the size of human antibodies. The llama’s antibody still forms a Y, but its arms are much shorter because it doesn’t have any light-chain proteins. This more diminutive antibody can access tinier pockets and crevices on spike proteins — the proteins that allow viruses like the novel coronavirus to break into host cells and infect us — that human antibodies cannot. That can make it more effective in neutralizing virusesLlamas’ antibodies are also easily manipulated, said Dr. Xavier Saelens, a molecular virologist at Ghent University in Belgium and an author of the new study. They can be linked or fused with other antibodies, including human antibodies, and remain stable despite those manipulations.

Source: https://www.cell.com/
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