Parkinson’s research: Experimental nanobody targets toxic proteins
- 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 millionTrusted Source 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 levelsTrusted Source, low norepinephrine levelsTrusted Source, and clumps of a protein called alpha-synucleinTrusted Source 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 nanobodyTrusted Source 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 CommunicationsTrusted Source.
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Treatment for Parkinson’s Disease
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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 transmissionTrusted Source 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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Medical Myths: All about Parkinson’s disease
April is Parkinson’s Awareness Month. With this in mind, this week’s edition of Medical Myths tackles the many misunderstandings that surround Parkinson’s disease. We discuss the symptoms and treatment, the outlook for people with the condition, and more.
Parkinson’s disease is a neurodegenerative movement disorder. Over time, dopamine-producing cells in a part of the brain called the substantia nigraTrusted Source deteriorate.
This deterioration, which leads to a reduction in dopamine, produces symptoms. The symptoms tend to develop slowly over time, often starting with a slight tremor in one hand or stiffness in movement.
Aside from tremor and stiffness, other symptoms include difficulties coordinating movements, changes in posture, a fixed facial expression, a reduced sense of smell, mood changes, and sleep problems.
As the disease progresses, some people with Parkinson’s develop dementia.
In 2016, an estimated 6.1 millionTrusted Source people worldwide had Parkinson’s disease. The number of cases has more than doubled in the last 25 years.
In this article, we dispel some of the most common myths associated with Parkinson’s disease.
Article highlights:
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It is true that the medical community considers Parkinson’s disease a motor disorder. However, people with the condition often also experience nonmotor symptoms, which can begin before the motor symptoms.
Nonmotor symptoms can include cognitive impairment or dementia, depression and anxiety, sleep dysfunction, pain, apathy, sexual dysfunction, and bowel incontinence.
People often overlook these symptoms, but they are important. As the authors of one paper on the topic explain:
“[N]onmotor symptoms dominate the clinical picture of advanced Parkinson’s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy.”
Although there is no cure for Parkinson’s disease, drugs can help people manage the condition. One of the most effectiveTrusted Source drugs is levodopa, which the body converts into dopamine once it enters the brain.
There is a long standing myth that levodopa can only relieve symptoms for about 5 years before it stops working. This is a myth. Levodopa can be effective for decades. However, over time, its effectiveness might reduce.
Medical News Today spoke with James Beck, Senior Vice President and Chief Scientific Officer of the Parkinson’s Foundation. He explained why levodopa becomes less potent:
“One of the cruel ironies about Parkinson’s disease is that the key enzyme that converts levodopa to dopamine (aromatic acid decarboxylase or AADC) is predominantly found in the dopamine neurons of the substantia nigra, which are lost during progression of the disease. So, the main way to make dopamine available to the Parkinson’s brain declines as the disease advances.”
In other words, it is not that levodopa stops being effective. Instead, the supply of the enzyme that it needs to be effective becomes more limited.
In the past, doctors and people with Parkinson’s have held off starting treatment because of fears that levodopa would slowly stop working. We now know, though, that this reduction in potency is due not to the length of time that a person takes levodopa but to the progression of the disease.
However, it is true that over time, each dose of levodopa might improve symptoms for a shorter period. This so-called wearing-offTrusted Source means that symptoms start to return before the next dose is due.
Another misconception about levodopa is that it can make Parkinson’s disease symptoms worse. This is not true.
It is important to note that levodopa can cause other motor symptoms, such as dyskinesia, which refers to involuntary jerky movements. However, the onset of dyskinesia is relatedTrusted Source to the progress of the underlying disease rather than how long an individual has been taking levodopa.
Therefore, doctors no longer recommend holding off on taking levodopa until later in the disease.
According to the American Parkinson’s Disease Association (APDA), dyskinesia does not generally appear until the individual has been taking levodopa for 4–10 years. The APDA also writes:
“Dyskinesia in its milder form may not be bothersome, and the mobility afforded by taking levodopa may be preferable to the immobility associated with not taking levodopa. People with Parkinson’s must weigh the benefits from using levodopa versus the impact of dyskinesia on their quality of life.”
Tremor is the most well-known symptom of Parkinson’s disease. However, it can also occur as part of other conditions, including drug-induced parkinsonism, vascular parkinsonism, dystonic or essential tremor, psychogenic disease, and dopa-responsive dystonia.
Although doctors understand the range of symptoms that are associated with Parkinson’s, it is very difficult to predict how an individual’s disease will progress. Parkinson’s varies substantially among individuals.
As the authors of one study explain, there are “radical differences in clinical manifestations and progression between patients.”
“The [reason for the] differences observed in how individuals experience Parkinson’s disease and its progression remains unknown.” Dr. Beck explained to MNT. “It could be based on how Parkinson’s began with each individual.”
Scientists are currently investigatingTrusted Source ways of making better predictionsTrusted Source. Hopefully, in the future, doctors will be able to provide a clearer idea of how an individual’s condition will progress.
Tremor is perhaps one of the most recognizable symptoms of Parkinson’s disease. However, some people develop nonmotor symptoms before tremor appears.
Also, some individuals do notTrusted Source experience tremor at any point during the disease’s progression.
Speaking with MNT, Dr. Beck explained, “About 20% of people with Parkinson’s disease do not develop a tremor.” Although scientists do not know why this is the case, Dr. Beck believes that tremor severity, in general, might depend on which brain regions the disease affects.
He noted that some scientists think “that people who have a strong tremor have lost more dopamine neurons in an area adjacent to the substantia nigra called the retrorubral area. It is these dopamine neurons (or their loss) that contribute to Parkinson’s tremor.”
In some conditions, such as multiple sclerosis, people can experience exacerbations, or flare-ups, of their symptoms. Parkinson’s disease, however, does not tend to work in this way.
The symptoms, overall, progress very slowly, although they might fluctuate throughout the day.
If someone’s symptoms do worsen suddenly, it is likely due to other factors. For instance, one studyTrusted Source investigated these types of exacerbations in 120 people with Parkinson’s over an 18-month period.
The most common cause was infection, accounting for more than 1 in 4 (25.6%) exacerbations. Other factors included anxiety, medication errors, poor adherence to medications, medication side effects, and a decline in health following surgery.
According to the authors, 81.4% of these episodes were “attributable to reversible or treatable causes.”
There is a persistent myth that drugs are the only way to ease symptoms or slow disease progression. This is a myth.
There is mounting evidence that staying physically active can reduce symptoms and potentially even slow disease progression.
The Parkinson’s Foundation explains that people with Parkinson’s “who start exercising earlier and [for] a minimum of 2.5 hours a week experience a slowed decline in quality of life compared [with] those who start later. Establishing early exercise habits is essential to overall disease management.”
Research suggests that exercise does not just reduce the motor symptoms of Parkinson’s. For instance, studies have found that exercise helps improve associated sleep problemsTrusted Source and cognitive functionTrusted Source in people with the condition.
This is a misconception. Parkinson’s is not fatal in the same way that a heart attack might be. People with Parkinson’s can live long and meaningful lives.
Compared with individuals who do not have Parkinson’s, those who do have the disease are likely to have a reduced life expectancy. This reduction is more significant for people who develop the disease at a younger age but less pronounced in those who do not develop dementia.
Although Parkinson’s is not fatal, it increases the risk of falls. Serious falls can be fatal, or they can require surgery, which increases the risk of complications or infections.
Another substantial risk is pneumonia. As people with Parkinson’s may have difficulty swallowing, they can inhale particles of food into the lungs. People with Parkinson’s also have weaker cough reflexes, so the food might stay in the lungs, where it can spark an infection.
The inability to cough out the infected material means that these infections can be fatal.
As the APDA explains, “Most patients die with Parkinson’s disease and not from it.”
Although there are still gaps in our knowledge about Parkinson’s disease, researchers continue to dive into the details. When MNT asked Dr. Beck about promising avenues of research, he said:
“I think genetic forms of Parkinson’s disease offer the best hope for treatments that may alter the course of the disease.” Scientists estimate that genetics are responsible for 10–15% of Parkinson’s cases.
“However, in order for any trial to succeed in targeting genetic Parkinson’s, we (patients and clinicians) need to know who carries disease-related mutations. Currently, no one really knows,” explained Dr. Beck.
“That is why the Parkinson’s Foundation launched PD GENEration, a national initiative that offers genetic testing and counseling at no cost for people with Parkinson’s disease. While this is not a cure for Parkinson’s now, our goals for PD GENEration are to accelerate clinical trials for the disease, improve Parkinson’s care and research, and empower people with Parkinson’s and their care teams.”
Slowly, researchers are unpicking the mechanisms at work in Parkinson’s, and, hopefully, they will one day identify more effective treatments and perhaps even a cure
