Breakthrough discovery of Parkinson’s disease gene reveals evolutionary origins

Parkinson’s disease is a progressive neurodegenerative movement disorder. It gradually impairs a person’s functioning until they eventually become immobile and often develop dementia. In the United States alone, more than one million people live with Parkinson’s disease, and new cases and total numbers are steadily increasing.

There are currently no treatments to slow or stop Parkinson’s disease. Existing drugs cannot slow disease progression and can only treat certain symptoms. However, drugs that work early in the disease, such as levodopa, often become less effective over time and require increased doses, which can lead to disabling side effects.

Without understanding the underlying molecular causes of Parkinson’s disease, it’s impossible for researchers to develop a drug that could halt the progression of the disease in patients.

Many factors may contribute to the development of Parkinson’s disease, including environmental factors and genetic factors. Until recently, the underlying genetic cause of the disease was 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 devoted my career to predicting and preventing Parkinson’s disease.

In our newly published research, my team and I discovered a new genetic variant associated with Parkinson’s disease that sheds light on the evolutionary origins of multiple forms of familial Parkinson’s disease and provides new insights into how to better understand and Treating the disease opens doors.

Genetic links and associations

In the mid-1990s, researchers began studying whether genetic differences between people with and without Parkinson’s disease might identify specific genes or genetic variants that contribute to the disease. Generally speaking, I and other geneticists use two methods to map the genetic blueprint of Parkinson’s disease: linkage analysis and association studies.

The association analysis focused on rare families who inherit Parkinson’s disease or neurological disorders with symptoms similar to Parkinson’s disease. The technique looks for cases where the disease-causing version of the gene and Parkinson’s disease appear to be inherited in the same person. It requires information about your family tree, clinical data and DNA samples.

It takes relatively few families, such as those with more than two living affected relatives willing to participate, to speed up new genetic discoveries.

The “association” between pathogenic genetic variants and disease development is important and can inform diagnosis. It has also become the basis for many laboratory models used to study the consequences of gene dysfunction and how to repair it. Linkage studies, such as the one my team and I published, have identified disease-causing mutations in more than 20 genes.

It is important to note that many people with Parkinson’s disease families have symptoms that are indistinguishable from classic late-onset Parkinson’s disease. However, the cause of hereditary Parkinson’s disease (which typically affects people with early-onset disease) may not be the cause of Parkinson’s disease in the general population.

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In contrast, genome-wide association studies (GWAS) compare genetic data from people with Parkinson’s disease to genetic data from unrelated people of the same age, gender and race who do not have the disease.

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

Although costly and time-consuming, the results of genome-wide association studies have broad applicability. Combining data from these studies, we identified a number of locations in the genome that contribute to Parkinson’s disease risk.

Currently, more than 92 locations in the genome contain approximately 350 genes that may be involved in disease. However, GWAS locations can only be considered collectively; individual results are not helpful for diagnosis or disease modeling because the contribution of these individual genes to disease risk is so small.

Together, the findings of “correlation” and “association” mean that many molecular pathways are involved in Parkinson’s disease. Each identified gene and the protein it encodes can often produce more than one effect. The function of each gene and protein may also vary between cell types. The question is which genetic variants, functions and pathways are most relevant to Parkinson’s disease? How can researchers meaningfully connect this data?

Parkinson’s disease gene

Through linkage analysis, my team and I discovered a new genetic mutation in Parkinson’s disease called RAB32 Ser71Arg. The mutation has been linked to Parkinson’s disease in three families and has been found in 13 other people in several countries, including Canada, France, Germany, Italy, Poland, Turkey, Tunisia, the United States and the United Kingdom.

Although affected individuals and families come from many parts of the world, they share the same segment of chromosome 6 that contains RAB32 Ser71Arg. This shows that these patients are all related to the same person; ancestrally, they are distant cousins. It also shows that there are many more cousins ​​that need to be identified.

Through further analysis, we found that RAB32 Ser71Arg interacts with several proteins previously associated with early-onset and late-onset Parkinson’s disease, as well as non-familial Parkinson’s disease. RAB32 Ser71Arg variants also cause similar dysfunction within cells.

The proteins encoded by these linked genes work together to 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 autophagy processes. Furthermore, these encoded proteins enable intracellular immunity.

These linked genes support the idea that these causes of inherited Parkinson’s disease evolved to improve survival early in life because they enhance immune responses to pathogens. RAB32 Ser71Arg shows how and why many mutations originate despite creating a predisposing genetic background for Parkinson’s disease later in life.

RAB32 Ser71Arg is the first linked gene discovered by researchers that directly connects the dots between previous linkage discoveries. The encoded protein brings together three important functions of the cell: autophagy, immunity, and mitochondrial function.

While autophagy releases energy stored in cellular waste, this requires coordination with another specialized component within the cell: mitochondria, the primary supplier of energy. Mitochondria also help control cellular immunity because they evolved from bacteria, which the cell’s immune system recognizes as “self” rather than as invading pathogens to be destroyed.

Identify subtle genetic differences

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

Just as each brand of motor is slightly different, so are the factors that make each person genetically susceptible to non-familial Parkinson’s disease.

However, analyzing genetic data can now test for the type of cellular dysfunction that is a hallmark of Parkinson’s disease. This will help researchers identify environmental factors that influence Parkinson’s risk, as well as drugs that can help prevent the disease.

More patients and families will need to participate in genetic research to find other components of the engine behind Parkinson’s disease. Each person’s genome is made up of the 6 billion building blocks that make up his or her genes, with approximately 27 million variations among them. There are many more genetic components to Parkinson’s disease that have yet to be discovered.

As our findings illustrate, each new gene researchers discover could dramatically 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.