Clumps of misfolded proteins that gather in the brain have been linked to neurodegenerative diseases like Parkinson’s. Now, newly identified nanobodies show promise in destabilizing the structure of these clumps, potentially leading to new treatments for the disease.
The protein at the center of the study is known as alpha-synuclein. Alone it’s thought to play important roles in the brain, but it can fold incorrectly and clump together into what are known as Lewy bodies. These can affect the function of neurons and even begin to kill them, and have been implicated in neurological disorders like Parkinson’s disease.
Much of the research into Parkinson’s has focused on these Lewy bodies, exposing the protein’s “double life,” how the clumps may first form in the gut before making their way to the brain, or even whether it’s an autoimmune disease. Other teams have taken aim at Lewy bodies with artificial enzymes or refined peptides, with promising results.
For the new study, researchers at Johns Hopkins Medicine and the University of Michigan, Ann Arbor, investigated using nanobodies to break down Lewy bodies. Nanobodies are smaller versions of antibody proteins, which are used by the immune system to track down pathogens. Their smaller size allows them to squeeze through the membranes of brain cells, where they can bind to and break down alpha-synuclein clumps.
Normally, these nanobodies would break down inside the cells, so the team engineered them to lack certain chemical bonds that are vulnerable to this process. They found that this kept the nanobodies stable without reducing their ability to bind to alpha-synuclein clumps.
After testing seven versions of their 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 be stable and strongly bound to the protein clumps, effectively breaking them down.
“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,” said Ramhari Kumbhar, co-first author of the study.
Importantly, the team found that the nanobodies only attacked alpha-synuclein clumps, not the individual molecules that likely perform vital functions in brain cells.
“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 Xiabo Mao, lead author of the study.
The research was published in the journal Nature Communications.