President Joe Biden.
| Photo Credit: AP

The White House sparred with reporters on July 8 over a Parkinson’s specialist visiting the building eight times in eight months, as reflected in the visitors’ log.

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“I am feeling a little miffed around here about how information has been shared with the press corps by him,” a reporter asked White House Press Secretary Karine Jean-Pierre during her daily news conference.

The White House visitors’ log suggests that Parkinson’s specialist Dr. Kevin Cannard visited the building eight times in eight months.

The reporters wanted to know if President Joe Biden was seen by the Parkinson’s specialist.

“It does not matter how hard you push me, it does not matter how angry you get with me, I am not going to confirm a name. It does not matter if it is even in the log. I am not going to do that from here. What I can share with you is that the President has seen a neurologist for his physical three times,” Ms. Jean-Pierre told the reporters.

“It is more than what the last guy shared and it is in line with what George W. Bush did. It is in line with what (Barack) Obama did. And so it is comprehensive. It is out there….

“I am not going to devolve somebody’s name or confirm someone. I am not going to do that. That is— as a privacy for that person. I am not going to do that. It does not matter how hard you push me. It does not matter how angry you get with me from here. I am just not going to do that. It is inappropriate and it is not acceptable, so I am not going to do it,” Ms. Jean-Pierre said.

Mr. Biden, she said, has seen a neurologist three times.

“No findings, which would be consistent with any cerebellar or other central neurological disorders such as stroke, multiple sclerosis, Parkinson’s or ascending lateral sclerosis that is coming from February,” she added.

“That is what the medical unit, the President’s doctor shared and I shared, I said to you it has happened three times each time. There is a physical that occurs and we put out a comprehensive report, that is when he has been able to see— to see a specialist. So that is what I can share,” Ms. Jean-Pierre said.

Synuclein alpha (SNCA) is a mysterious protein. It’s present in healthy cells but we don’t know what it does there. It is notorious for its involvement in age-related neurodegenerative diseases. Twenty-seven years ago, researchers first associated SNCA with Parkinson’s disease. People with this disease lose neurons that communicate with each other using dopamine as a neurotransmitter in a part of their brains.

These dopaminergic neurons have been found to contain aggregated masses of proteins called Lewy bodies. Most of these proteins are SNCA.

Since then, researchers have reported SNCA in similar aggregates in the brains of people with other neurodegenerative diseases as well. But its presence is most prominent in brains with Parkinson’s.

SNCA is abundant in neurons, especially in dopaminergic neurons. It is found near the nuclei of these cells and at the junctions between two neurons. It’s capable of misfolding as well as forming filamentous structures. So unlike most other proteins, which take up predictable three-dimensional structures, SNCA can fold in multiple ways. Misfolded proteins don’t function correctly.

But beyond these observations, researchers don’t understand the dynamics of the formation of these aggregates and how exactly they affect neurons.

Two populations

A recent study from Swasti Raychaudhuri’s lab at the CSIR-Centre for Cellular and Molecular Biology, Hyderabad, published in the Journal of Cell Science, reported two ways in which SNCA is present as aggregates in cells: one that interferes with the structural integrity of cells’ nuclei and another that allows the cell to degrade misfolded proteins. The researchers found that the former are related to diseased states while the latter is important for healthy cells.

As such, the study highlights the importance of striking a balance between these two SNCA populations to manage Parkinson’s disease.

The researchers cultivated neurons outside a living body, providing them with nutrients in a laboratory setup. In these neurons, they artificially created structures resembling Lewy bodies by adding some amount of misfolded SNCA, called seeds.

Over time, they found two SNCA populations in the cells: one was around the nuclei, shaped like filaments tens of micrometres long, much like Lewy bodies. The other population was also around the nuclei but as much smaller clumps called aggresomes. Such aggresomes are formed when cells localise misfolded proteins into a small bunch (like collecting the trash in a corner) for further processing.

Breaching the nucleus

They noticed that the Lewy-body-like structures formed very slowly. Most of the time, the aggresomes took up the SNCA proteins and didn’t allow the Lewy-body-like structures to grow. But in their experiment, when the researchers repeatedly seeded neurons with misfolded SNCA, the Lewy-body-like structures formed faster and became big enough to affect other parts of the cell. At one point, they became too populous for the aggresomes to mitigate their prevalence.

The enlarged Lewy-body-like structures were situated at the periphery of the nuclei of the cells, and the researchers have argued that this damages the nuclear envelope. Sometimes, the structures also entered the ruptured nucleus.

A nucleus is the control centre of the cell. It contains the cell’s genetic material, and is the seat of upkeep of this genetic material and its utilisation to make proteins. So it is logical that the accumulation of misfolded SNCA would render the nucleus dysfunctional and eventually kill it. In addition, Lewy-body-like structures can pass from one cell to another, so the effect could cascade to neighbouring cells as well.

Dr. Raychaudhuri’s team was able to cross-check its findings in mice with Lewy-body-like structures in their brains. They reported that the increasing prevalence of these structures induced conditions mimicking Parkinson’s disease. They also found that all the cells so affected also had damaged nuclear envelopes.

A therapeutic target?

Many Parkinson’s disease researchers are focused on reducing the prevalence of SNCA in neurons as a therapeutic measure. Researchers are going about this in various ways, but haven’t yet found one that has been approved for sale.

One way is to reduce the cells’ SNCA content. A smaller population of SNCA means fewer misfolded SNCA, too. Researchers have achieved this by stopping the SNCA gene from expressing itself or by destroying the SNCA protein inside cells, once the cells make them. However, either of these interventions needs to happen only in select locations: if all the SNCA everywhere is taken away, the animal body will die.

Another workable solution has been to use a gene-silencing tool, like CRISPR-Cas9, at a precise location. Researchers have tried this method in cell cultures and model animals. But a significant challenge is to cross the blood-brain barrier, a liquid that filters the blood that goes into the brain, and which would also prevent a component CRISPR from passing through.

To surmount this barrier, some researchers have tried to inject molecules that inhibit the SNCA gene through the skull, directly into the desired brain region. Others have used small molecules like modified viruses to beat the barrier. Some researchers have also identified enzymes that degrade proteins in select brain cells, but with varying efficacy.

Another possibility is to stop SNCA from forming large aggregates. Dr. Raychaudhuri has suggested balancing the SNCA population between aggresomes and Lewy bodies. The more SNCA that goes into the aggresomes, the less there will be available to make Lewy bodies. How this can be achieved is still being worked out.

Even if any one of these methods succeeds, it will transform the way Parkinson’s disease is treated today. Today, Parkinson’s is treated symptomatically by increasing the levels of dopamine or, more drastically, by grafting new neurons in place of dead ones. An SNCA-based solution is more desirable because it offers a more sustainable resolution.

Somdatta Karak, PhD heads science communication and public outreach at CSIR-Centre for Cellular and Molecular Biology.

Parkinson’s disease is a neurodegenerative movement disorder that progresses relentlessly. It gradually impairs a person’s ability to function until they ultimately become immobile and often develop dementia. In the U.S. alone, over a million people are afflicted with Parkinson’s, and new cases and overall numbers are steadily increasing.

There is currently no treatment to slow or halt Parkinson’s disease. Available drugs don’t slow disease progression and can treat only certain symptoms. Medications that work early in the disease, however, such as Levodopa, generally become ineffective over the years, necessitating increased doses that can lead to disabling side effects. Without understanding the fundamental molecular cause of Parkinson’s, it’s improbable that researchers will be able to develop a medication to stop the disease from steadily worsening in patients.

Many factors may contribute to the development of Parkinson’s, both environmental and genetic. Until recently, underlying genetic causes of the disease were unknown. Most cases of Parkinson’s aren’t inherited but sporadic, and early studies suggested a genetic basis was improbable.

Nevertheless, everything in biology has a genetic foundation. As a geneticist and molecular neuroscientist, I have devoted my career to predicting and preventing Parkinson’s disease. In our newly published research, my team and I discovered a new genetic variant linked to Parkinson’s that sheds light on the evolutionary origin of multiple forms of familial parkinsonism, opening doors to better understand and treat the disease.

Genetic linkages and associations

In the mid-1990s, researchers started looking into whether genetic differences between people with or without Parkinson’s might identify specific genes or genetic variants that cause the disease. In general, I and other geneticists use two approaches to map the genetic blueprint of Parkinson’s: linkage analysis and association studies.

Linkage analysis focuses on rare families where parkinsonism, or neurological conditions with similar symptoms to Parkinson’s, is passed down. This technique looks for cases where a disease-causing version of the gene and Parkinson’s appear to be passed down in the same person. It requires information on your family tree, clinical data and DNA samples. Relatively few families, such as those with more than two living, affected relatives willing to participate, are needed to expedite new genetic discoveries.

“Linkage” between a pathogenic genetic variant and disease development is so significant that it can inform a diagnosis. It has also become the basis of many lab models used to study the consequences of gene dysfunction and how to fix it. Linkage studies, like the one my team and I published, have identified pathogenic mutations in over 20 genes. Notably, many patients in families with parkinsonism have symptoms that are indistinguishable from typical, late-onset Parkinson’s. Nevertheless, what causes inherited parkinsonism, which typically affects people with earlier-onset disease, may not be the cause of Parkinson’s in the general population.

Conversely, genome-wide association studies, or GWAS, compare genetic data from patients with Parkinson’s with unrelated people of the same age, gender and ethnicity who don’t have the disease. Typically, this involves assessing how frequently in both groups over 2 million common gene variants appear. Because these studies require analyzing so many gene variants, researchers need to gather clinical data and DNA samples from over 100,000 people.

Although costly and time-consuming, the findings of genome-wide association studies are widely applicable. Combining the data of these studies has identified many locations in the genome that contribute to the risk of developing Parkinson’s. Currently, there are over 92 locations in the genome that contain about 350 genes potentially involved in the disease. However, GWAS locations can be considered only in aggregate; individual results are not helpful in diagnosis nor in disease modeling, as the contribution of these individual genes to disease risk is so minimal.

Together, “linked” and “associated” discoveries imply a number of molecular pathways are involved in Parkinson’s. Each identified gene and the proteins they encode typically can have more than one effect. The functions of each gene and protein may also vary by cell type. The question is which gene variants, functions and pathways are most relevant to Parkinson’s? How do researchers meaningfully connect this data?

Parkinson’s disease genes

Using linkage analysis, my team and I identified a new genetic mutation for Parkinson’s disease called RAB32 Ser71Arg. This mutation was linked to parkinsonism in three families and found in 13 other people in several countries, including Canada, France, Germany, Italy, Poland, Turkey, Tunisia, the U.S. and the U.K.

Although the affected individuals and families originate from many parts of the world, they share an identical fragment of chromosome 6 that contains RAB32 Ser71Arg. This suggests these patients are all related to the same person; ancestrally, they are distant cousins. It also suggests there are many more cousins to identify.

With further analysis, we found RAB32 Ser71Arg interacts with several proteins previously linked to early- and late-onset parkinsonism as well as nonfamilial Parkinson’s disease. The RAB32 Ser71Arg variant also causes similar dysfunction within cells.

Together, the proteins encoded by these linked genes optimize levels of the neurotransmitter dopamine. Dopamine is lost in Parkinson’s as the cells that produce it progressively die. Together, these linked genes and the proteins they encode regulate specialized autophagy processes. In addition, these encoded proteins enable immunity within cells.

Such linked genes support the idea that these causes of inherited parkinsonism evolved to improve survival in early life because they enhance immune response to pathogens. RAB32 Ser71Arg suggest how and why many mutations have originated, despite creating a susceptible genetic background for Parkinson’s in later life.

RAB32 Ser71Arg is the first linked gene researchers have identified that directly connects the dots between prior linked discoveries. The proteins encoded bring together three important functions of the cell: autophagy, immunity and mitochondrial function. While autophagy releases energy stored in the cell’s trash, this needs to be coordinated with another specialized component within the cell, mitochondria, that are the major supplier of energy. Mitochondria also help to control cell immunity because they evolved from bacteria the cell’s immune system recognizes as “self” rather than as an invading pathogen to destroy.

Identifying subtle genetic differences

Finding the molecular blueprint for familial Parkinson’s is the first step to fixing the faulty mechanisms behind the disease. Like the owner’s manual to your car’s engine, it provides a practical guide of what to check when the motor fails.

Just as each make of motor is subtly different, what makes each person genetically susceptible to nonfamilial Parkinson’s disease is also subtly different. However, analyzing genetic data can now test for types of dysfunction in the cell that are hallmarks of Parkinson’s disease. This will help researchers identify environmental factors that influence the risk of developing Parkinson’s, as well as medications that may help protect against the disease.

More patients and families participating in genetic research are needed to find additional components of the engine behind Parkinson’s. Each person’s genome has about 27 million variants of the 6 billion building blocks that make up their genes. There are many more genetic components for Parkinson’s that have yet to be found.

As our discovery illustrates, each new gene that researchers identify can profoundly improve our ability to predict and prevent Parkinson’s.