A newly discovered genetic variant that causes Parkinson’s disease sheds light on what causes the disease and how to stop it.

Parkinson’s disease is a neuromotor disorder that progresses relentlessly. 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 one million people have Parkinson’s, and new cases and the total number are steadily increasing.

There is currently no treatment to slow or stop Parkinson’s disease. Existing drugs do not slow the progression of the disease and can only treat certain symptoms. Drugs that work early in the disease, such as levodopa, usually become ineffective over the years and require increased dosages, which can lead to debilitating side effects. Without understanding the underlying molecular cause of Parkinson’s, it is unlikely that researchers will be able to develop a drug to prevent the disease from steadily worsening in patients.

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

However, everything in biology has a genetic basis. As a geneticist and molecular neuroscientist, I have dedicated my work to the prediction and prevention of Parkinson’s disease. In our newly published research, my team and I discovered a new genetic variant associated with Parkinson’s that sheds light on the evolutionary origins of multiple forms of familial parkinsonism and opens doors to better understanding and treatment of the disease.

Links and genetic connections

In the mid-1990s, researchers began investigating whether genetic differences between people with and 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 Parkinson’s genetics: linkage analysis and association studies.

Linkage analysis focuses on rare families in which parkinsonism or neurological conditions with symptoms similar to parkinsonism are transmitted. The method looks for cases where the pathogenic version of the gene and Parkinson’s appear to be passed on in the same person. This requires pedigree information, clinical data and DNA samples. Relatively few families, such as those with more than two affected relatives willing to participate, are needed to accelerate new genetic discoveries.

The “association” between a pathogenic genetic variant and the development of the disease is so important that it can indicate the diagnosis. It is also the basis of many laboratory models used to study the consequences of gene dysfunction and how to fix it. Linkage studies, such as the one my team and I published, have identified pathogenic mutations in more than 20 genes. Notably, many patients in families with Parkinson’s disease have symptoms that are indistinguishable from typical late-onset Parkinson’s disease. However, what causes hereditary parkinsonism, which usually affects people with early-onset disease, may not be the cause of parkinsonism in the general population.

Conversely, genome-wide association studies, or GWAS, compare the genetic data of patients with Parkinson’s disease with unrelated individuals of the same age, sex, and ethnicity who do not have the disease. Typically, this involves evaluating the frequency of occurrence of more than 2 million common gene variants in both groups. Because these studies require the analysis of many gene variants, the researchers must collect clinical data and DNA samples from more than 100,000 people.

Although costly and time-consuming, findings from genome-wide association studies are widely applicable. Combining data from these studies has identified many locations in the genome that contribute to Parkinson’s risk. Currently, there are more than 92 sites in the genome that contain about 350 genes potentially involved in this disease. However, GWAS loci can only be considered in aggregate. Individual results are not useful in disease diagnosis and modeling because the contribution of these individual genes to disease risk is very small.

Together, the “correlated” and “correlated” discoveries suggest that a number of molecular pathways are involved in Parkinson’s. Each identified gene and the proteins it encodes can usually have more than one effect. The function of each gene and protein may also be different depending on the type of cell. The question is, which gene variants, functions and pathways are most associated with Parkinson’s? How do researchers meaningfully link these data together?

Parkinson’s disease genes

Using linkage analysis, my team and I identified a novel genetic mutation for Parkinson’s disease, RAB32 Ser71Arg. The mutation was associated with parkinsonism in three families and was found in 13 others in several countries, including Canada, France, Germany, Italy, Poland, Turkey, Tunisia, the United States, and the United Kingdom.

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

Upon further analysis, we found that RAB32 Ser71Arg interacts with several proteins previously associated with early-onset and late-onset parkinsonism as well as non-familial parkinsonism. The RAB32 Ser71Arg variant also causes similar dysfunction in cells.

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

Such linked genes support the idea that these causes of inherited parkinsonism have evolved to improve survival early in life by enhancing the immune response to pathogens. RAB32 Ser71Arg shows how and why many mutations arise despite creating a genetic background that predisposes to Parkinson’s later in life.

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

Identify subtle genetic differences

Finding the molecular blueprint of familial Parkinson’s disease is the first step toward unraveling the faulty mechanisms behind the disease. Like the owner’s manual for your car’s engine, it provides practical guidance on what to check if the engine fails.

Just as each motor is subtly different, what makes each person genetically predisposed to non-familial Parkinson’s disease is also subtly different. However, analysis of genetic data can now test for the types of cell abnormalities that are symptoms of Parkinson’s disease. This will help researchers identify environmental factors that affect the risk of developing Parkinson’s, as well as drugs that may help protect against the disease.

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

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