Parkinson’s research: Experimental nanobody targets toxic proteins

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Could an experimental nanobody change the future of Parkinson’s therapy? Image credit: Andriy Onufriyenko/Getty Images,
  • Parkinson’s disease is a progressive, neurodegenerative condition that is increasing in prevalence worldwide.
  • There is currently no cure for the condition, which causes tremors, muscle weakness, and mood changes.
  • Now, scientists have designed a nanobody that can untangle the misshapen proteins in the brain that lead to many of the symptoms of Parkinson’s.
  • This finding could be key to studying the disease and developing new treatments.

Parkinson’s disease (PD) affects at least 8.5 million people worldwide, most of them aged over 60. According to the World Health Organization (WHO), the number has more than doubled in the past 25 years.

Diagnosis is difficult in the early stages as many of the symptoms may indicate other disorders, so these numbers are almost certainly an underestimate.

Common symptoms include tremors, muscle rigidity, and slowness of movement. Some people also experience pain, anxiety, and depression.

Currently, there is no cure for PD, although existing treatments can help manage the symptoms and improve quality of life.

A number of factors are responsible for the symptoms, such as low dopamine levels, low norepinephrine levels, and clumps of a protein called alpha-synuclein in the brain.

These clumps form the structural core of Lewy bodies, which cause a loss of nerve cells, leading to changes in movement, thinking, behavior, and mood that are the main symptoms of PD.

Now, scientists from Johns Hopkins University have genetically engineered a nanobody to target alpha-synuclein clumps in the brain and destabilize them. The research could lead to new treatments for Parkinson’s disease.

They report their findings in Nature Communications.

Nanobodies, or single-domain antibodies, are the smallest fragment of an antibody with binding ability. They are highly stable and can penetrate into tissues.

Dr. Melita Petrossian, neurologist, and director of the Movement Disorders Center at Providence Saint John’s Health Center in Santa Monica, CA, told Medical News Today:

“Compared to a traditional antibody, a nanobody is about 90% smaller and therefore better able to enter a cell. This is important because much of the alpha-synuclein pathology is found intracellularly — inside the brain cells — so nanobodies would be expected to be more effective against PD than traditional antibodies.”

In this study, researchers genetically modified a nanobody that could get through the tough exterior of brain cells. By removing disulfide bonds in the nanobody, they ensured that it remained stable once inside the brain cells, allowing it to bind with alpha-synuclein clumps.

The advantage of this nanobody, named PFFNB2, is that it binds only to the alpha-synuclein clumps that cause the symptoms of Parkinson’s disease.

It does not bind to single molecules of alpha-synuclein that researchers believe to be important in the transmission of nerve impulses.

Initially, the researchers tested the nanobody on mouse brain tissue in vitro. They found that PFFNB2 could bind to aggregates of alpha-synuclein, but could not prevent the formation of clumps.

Further experiments revealed that the nanobody could bind to and disrupt fibrils of alpha-synuclein that had already formed, destabilizing the misshapen proteins.

The researchers then tested this in live mice and found that the nanobody prevented alpha-synuclein from spreading to the cortex of the brain. The cortex is the largest part of the brain and is responsible for most higher brain functions.

Dr. Petrossian explained for MNT that “[t]he results showed that they were able to specifically target the preformed fibrils of alpha-synuclein in cell and mouse models, that they were able to reduce the clumping (aggregation) of alpha-synuclein in cell models, and they were able to reduce alpha-synuclein pathology in mouse models.”

Dr. Xiaobo Mao, lead researcher of the study, and associate professor of neurology at Johns Hopkins University, notes the following about the clinical potential of this discovery:

“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.”

According to the authors, these findings could be a big step forward in the search for effective treatments for PD and related disorders. “We expect that these PFFNB-related agents hold great promise as a potential therapeutic strategy against [alpha-synuclein]-related pathogenesis,” they write.

Dr. Petrossian agreed. “If these results are borne out in human clinical trials, it is very likely that these nanobodies will be a very important component of treatment of PD and DLB [dementia with Lewy bodies], alongside lifestyle choices such as exercise and healthy diet,” she told us.

“I am hopeful that the researchers will be able to organize a clinical trial in humans soon, but we will need to see the safety, tolerability, and efficacy in humans before nanobodies can reach the general population,” she added.

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