How to inhibit brain toxicity

Scientists attempt to decipher molecules capable of interrupting neurological processes related to diseases such as cancer and Parkinson’s

Eduardo Geraque

Research groups around the world committed to unraveling the intricacies of the biochemistry behind diseases like Parkinson’s are drawing attention to compounds found naturally in the blood of certain animals, including llamas and sharks. While the human immune system has an army of antibodies ready and waiting to seek out and destroy invading microorganisms, these camelids and great predators of the deep sea have their own defense mechanism called nanobodies, like smaller versions of our antibodies.

One line of research into these molecules has demonstrated that they can play an important role in interrupting toxic neurological processes related to certain types of tumors and autoimmune diseases, including Parkinson’s and dementia with Lewy bodies—clusters of a specific protein called alpha-synuclein that form inside and eventually kill neurons. The theory was reinforced by a recent study whose findings were published in the journal Nature Communications.

Scientists from the Johns Hopkins School of Medicine and the University of Michigan, USA, have developed a nanobody capable of acting directly on rodent brains. The compound is able to pass through resistant brain cells to directly affect the alpha-synuclein inside. It has also been linked to diseases such as Parkinson’s in several other studies. The researchers, however, found an additional problem: because this protein occurs naturally in the brain, it also plays a role in healthy and important neurological processes.

Neurodegenerative disorders related to alpha-synuclein identified by other research groups begin to occur when the protein becomes tangled together into toxic clumps. The final consequence of this process is death of the neuron. Scientific evidence has also shown that alpha-synuclein clusters can travel from the intestine or nose to the brain, leading to the progression of neurodegenerative diseases. According to the researchers, the new nanobodies are more able to punch through the tough exterior of the brain cells than antibodies, which are larger.

The nanobodies developed by the Johns Hopkins team and colleagues were genetically modified so that they behave more stably in rodent brains and bind exclusively to the alpha-synuclein clusters. The scientists made seven types of nanobodies, one of which proved effective.

“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, a postdoctoral researcher at Johns Hopkins and one of the authors of the scientific article.

“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, an associate professor of neurology who also participated in the study.

Reservations

While this scientific advance represents another step toward understanding neurodegenerative diseases and improving quality of life for people who suffer from them, there is still plenty more work to be done, as attested by Susan Chien Hsin Fen, a neurologist from the University of São Paulo (USP). “Nanobodies have a promising future, but I have some reservations about the relationship between them and Parkinson’s disease, more specifically,” says the researcher.

She highlights that although many studies have already been published on the subject—and she describes the study carried out at Johns Hopkins as elegant—it is still unknown whether there is a relationship of cause and effect with alpha-synuclein or if it functions simply as a marker of cell death.

“Even if there is a relationship and the protein in question is inactivated, other proteins are also involved in the pathophysiology of the disease. Furthermore, this intervention [to turn off the protein clump] has to be made before it forms—before the individual develops the disease,” says Hsin Fen.

And there are other questions that still need to be answered, says the Brazilian doctor. “Since the nanobody is specifically for alpha-synuclein in animals, will the results be reproducible in humans? And where should the nanobodies be injected to ensure efficiency? Should they be applied to the central nervous system alone, or in other parts of the body too, since Parkinson’s is a systemic disease?”

According to the neurologist, these dilemmas are also applicable to other types of dementia, such as Alzheimer’s. In this case, she says, studies with monoclonal antibodies, such as “anti-amyloids” (amyloid is an insoluble protein that can be deposited in various tissues and can impair organ function), have not proven effective at treating the disease.

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