Johns Hopkins Scientists Have Developed a Nanobody That May Treat Parkinson’s Disease



Antibody proteins are used by the immune system to identify and combat invasive invaders. Researchers are looking into nanobodies, which are little antibodies found in the blood of animals like llamas and sharks, to treat cancer and autoimmune illnesses. Now, researchers from Johns Hopkins Medicine have contributed to the development of a nanobody that can pierce the protective layer that surrounds brain cells and separate misshaped proteins that are the root of conditions like Parkinson's disease, Lewy body dementia, and other neurocognitive issues.

The study, which was just published in the journal Nature Communications, was a collaboration between researchers from Johns Hopkins Medicine, working under the guidance of Xiaobo Mao, Ph.D., and researchers from the University of Michigan, Ann Arbor. They sought a new therapeutic approach that might focus on the abnormal proteins known as alpha-synuclein, which have a propensity to aggregate and obstruct the function of brain cells. According to recent studies, alpha-synuclein aggregates can travel from the nose or gut to the brain, increasing the progression of the disease.

Although pathogen-fighting substances have trouble accessing the outer layer of brain cells, antibodies may theoretically be able to target clumping alpha-synuclein proteins. The researchers used nanobodies, which are microscopic copies of antibodies, to penetrate the dense coverings on brain cells.

In the past, nanobodies created outside of the cell might not have the same function there. The nanobodies had to be strengthened as a result in order for them to stay stable inside a brain cell. In order to rid the nanobodies of the chemical linkages that ordinarily break down inside a cell, they genetically engineered them. Tests showed that the nanobody could nevertheless connect to misshaped alpha-synuclein and maintain stability even in the absence of the linkages.

The group created seven related forms of nanobodies called PFFNBs that may attach to alpha-synuclein aggregates. One of the nanobodies they produced, PFFNB2, did the best job of adhering to alpha-synuclein aggregates rather than individual molecules or alpha-synuclein monomers. Alpha-synuclein monomers are not toxic and may serve crucial functions in brain tissue. Additionally, the stability and functionality of the PFFNB2 nanobody inside brain cells had to be ascertained by the researchers. The scientists discovered that PFFNB2 was stable and exhibited a considerable affinity for aggregates of alpha-synuclein rather than individual alpha-synuclein monomers in live mouse brain cells and tissue.

Further studies in mice revealed that although the PFFNB2 nanobody cannot stop alpha-synuclein from clumping, it can disrupt and destabilize the structure of already formed clumps.

Ramhari Kumbhar, Ph.D., co-first author and postdoctoral fellow at the Johns Hopkins University School of Medicine, says, "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.

According to Mao, an associate professor of neurology, "the efficacy of PFFNB2 in binding damaging alpha-synuclein clumps in increasingly complex contexts suggests that the nanobody could be essential to helping scientists understand these disorders and ultimately find new treatments."

The Parkinson's Foundation, the National Institutes of Health, the University of Michigan, and the Maryland Stem Cell Research Foundation all provided funding for the study.

By JOHNS HOPKINS MEDICINE 

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