Parkinson’s disease-causing variant sheds light on why disease develops

Parkinson’s disease is a neurodegenerative movement disorder make unremitting progress. It gradually impairs a person’s functional abilities until they eventually become immobile and often develop dementia. In the United States alone, more than one million people have Parkinson’s disease. new cases and total is increasing steadily.

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 becomes ineffective over the years, requiring an increase in dosage, which can cause disabling side effects.without understanding basic molecular causes Parkinson’s researchers are unlikely to develop a drug that will halt patients’ progression of the disease.

Many factors may influence The development of Parkinson’s disease includes both environmental 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 research showed that a genetic basis was impossible.

However, everything in biology has a genetic basis.as a Geneticists and Molecular Neuroscientists, I have dedicated 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 disease This reveals the evolutionary origins of many forms of familial Parkinson’s disease, opening the door to a better understanding and treatment of the disease.

Genetic links and associations

mid 1990sThe researchers then began studying whether genetic differences between people with and without Parkinson’s 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.

linkage analysis Focus on rare families Parkinson’s disease, or a neurological disorder with symptoms similar to Parkinson’s disease, is passed down. The technique looks for cases in which the disease-causing 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.Correlation studies, e.g. My team and I published, It has been identified Pathogenic mutation in more than20 genes. It is important to note that many people with Parkinson’s disease families have symptoms that are indistinguishable from those of 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.

Genome-wide association studies examine genetic data from large populations.

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in turn, Genome-wide association studies (GWAS), comparing genetic data from people with Parkinson’s disease to genetic data from unrelated people of the same age, gender and race who don’t 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 has identified a number of location in genome This increases the risk of developing Parkinson’s disease.Currently, there are More than 92 locations in the genome Contains approximately 350 genes that may be related to the disease.However, GWAS locations can be Only comprehensive consideration; Individual results are not helpful for diagnosis or disease modeling because the contribution of these individual genes to disease risk is so small.

Taken together, the related findings imply 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 indicates that these patients are 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 previously linked proteins Arrive early——and late onset parkinsonism also non-family Parkinson’s Disease. RAB32 Ser71Arg mutations can also cause similar dysfunction in the cell.

These linked genes encode proteins that together Optimize levels of the neurotransmitter dopamine. People with Parkinson’s disease lose dopamine as the cells that produce it gradually die.These linked genes, along with the proteins they encode, adjust specialized Autophagy process.Furthermore, these encoded proteins are able to intracellular immunity.

These linked genes support the idea that these causes of inherited Parkinson’s disease evolved as Improve survival rates early in life because of them Enhance immune response against pathogens. RAB32 Ser71Arg shows how and why many mutations originate, despite the creation susceptibility genetic background For Parkinson’s later 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 needs to be coordinated with another specialized component within the cell: mitochondria, which are the main suppliers of energy.Mitochondria also help control cellular immunity because they evolved from bacteriaThe cellular immune system recognizes it as itself rather than as an invading pathogen to be destroyed.

Identify subtle genetic differences

Finding the molecular blueprint for familial Parkinson’s disease is the first step toward unraveling the faulty mechanisms underlying the disease. Like an owner’s manual for your car’s engine, 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 are needed to participate in genetic research to find other components of the engine behind Parkinson’s disease.Everyone’s genome has About 27 million variants The 6 billion building blocks that make up its genes. 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.

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Matthew Farrell is a professor of neurology at the University of Florida.This article is reproduced from dialogue in a Creative Commons License.read Source article.