Breakthrough Parkinson’s Gene Discovery Sheds Light on Evolutionary Origin : ScienceAlert

Parkinson’s disease is a neurodegenerative movement disorder that progresses unabated. This gradually impairs a person’s ability to function until they eventually become immobile and often develop dementia. In the United States alone, more than a million people suffer from Parkinson’s disease, and both new cases and the total number of cases are steadily increasing.

There is currently no treatment to slow or stop Parkinson’s disease. Available medications do not slow the progression of the disease and can only treat certain symptoms. However, medications that work early in the disease, such as levodopa, typically become ineffective over time, requiring increased doses that can cause disabling side effects.

Without understanding the fundamental molecular cause of Parkinson’s disease, it is unlikely that researchers will be able to develop a drug to prevent the disease from steadily worsening in patients.

Many factors can contribute to the development of Parkinson’s disease, both environmental and genetic. Until recently, the underlying genetic causes of the disease were unknown. Most cases of Parkinson’s disease are not hereditary but sporadic, and early studies suggested a genetic basis was unlikely.

However, everything in biology has a genetic basis. As a geneticist and molecular neuroscientist, I have dedicated my career to predicting and preventing Parkinson’s disease.

In our recently published research, my team and I discovered a new genetic variant linked to Parkinson’s disease that sheds light on the evolutionary origin of multiple forms of familial Parkinsonism, opening the door to better understanding and treatment of the disease.

Genetic links and associations

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

Linkage analysis focuses on rare families in which Parkinsonism, or neurological diseases with symptoms similar to Parkinson’s disease, are passed down. This technique looks for cases where a pathogenic version of the gene and Parkinson’s disease appears to be transmitted in the same person. It requires information about your family tree, clinical data and DNA samples.

Relatively few families, such as those with more than two living, affected parents willing to participate, are needed to accelerate new genetic discoveries.

The “link” between a pathogenic genetic variant and the development of the disease is so important that it can inform a diagnosis. It has also become the basis of many laboratory models used to study the consequences of genetic dysfunction and how to remedy it. Linkage studies, like the one my team and I published, have identified disease-causing mutations in more than 20 genes.

Notably, many patients from families with Parkinsonism present with symptoms indistinguishable from typical late-onset Parkinson’s disease. However, the cause of hereditary Parkinsonism, which usually affects people with early-onset disease, may not be the cause of Parkinson’s disease in the general population.

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Conversely, genome-wide association studies, or GWAS, compare the genetic data of Parkinson’s disease patients with that of unrelated people of the same age, gender, and ethnicity, who are not not affected by the disease.

Typically, this involves assessing the frequency of occurrence of more than 2 million common genetic variants in the two groups. Because these studies require the analysis of so many genetic variants, researchers must collect clinical data and DNA samples from more than 100,000 people.

Although costly and time-consuming, the findings of genome-wide association studies are widely applicable. Combining data from these studies has identified numerous locations in the genome that contribute to the risk of developing Parkinson’s disease.

Currently, there are more than 92 locations in the genome that contain approximately 350 genes potentially involved in disease. However, GWAS locations can only be considered globally; individual results are not useful for diagnosis or disease modeling because the contribution of these individual genes to disease risk is very minimal.

Together, the “related” and “associated” findings imply that a number of molecular pathways are involved in Parkinson’s disease. Each identified gene and the proteins they encode can typically have multiple effects. The functions of each gene and protein can also vary depending on the cell type. The question is, which genetic variants, functions and pathways are most relevant to Parkinson’s disease? How can researchers connect this data in a meaningful way?

Parkinson’s disease genes

Using linkage analysis, my team and I identified a new Parkinson’s disease genetic mutation 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 United States and the Kingdom -United.

Although 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 that these patients are all related to the same person; Ancestrally, they are distant cousins. This also suggests that there are many more cousins ​​to be identified.

With further analysis, we discovered that RAB32 Ser71Arg interacts with several proteins previously linked to early-onset and late-onset Parkinsonism as well as non-familial 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 disease as the cells that produce it gradually die. Together, these linked genes and the proteins they encode regulate specialized processes of autophagy. Additionally, these encoded proteins enable immunity within cells.

Such linked genes support the idea that these causes of hereditary parkinsonism evolved to improve survival early in life because they enhance the immune response to pathogens. RAB32 Ser71Arg suggests how and why many mutations arose, despite creating a genetic background likely to develop Parkinson’s disease later in life.

RAB32 Ser71Arg is the first linked gene identified by the researchers that directly connects the dots between previous linked findings. The encoded proteins bring together three important functions of the cell: autophagy, immunity and mitochondrial function.

While autophagy releases energy stored in the cell’s waste products, this must be coordinated with another specialized component of the cell, the mitochondria, which are the primary energy supplier. Mitochondria also help control cellular immunity because they evolved from bacteria that the cells’ immune system recognizes as “themselves” rather than as an invading pathogen to be destroyed.

Identifying subtle genetic differences

Finding the molecular model of familial Parkinson’s disease is the first step to correcting the faulty mechanisms that cause the disease. Just like your car’s engine owner’s manual, it provides a handy guide on what to check in the event of an engine failure.

Just as each brand of engine is subtly different, what makes each person genetically susceptible to non-familial Parkinson’s disease is also subtly different.

However, the analysis of genetic data now makes it possible to detect the types of cellular dysfunctions characteristic of Parkinson’s disease. This will help researchers identify environmental factors that influence the risk of developing Parkinson’s disease, as well as medications that could help protect against the disease.

It will take more patients and families participating in genetic research to uncover other components of the Parkinson’s disease driver. Each person’s genome has approximately 27 million variations of the 6 billion building blocks that make up their genes. There are still many other genetic components of Parkinson’s disease that have not yet been discovered.

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

Matthew Farrer, professor of neurology, University of Florida

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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