Parkinson’s disease is a relentlessly progressive neurodegenerative movement disorder. It gradually impairs a person’s ability to function until they eventually become immobile and often develop dementia. Over a million people in the United States alone have Parkinson’s disease, and new cases and overall numbers are rising.
There is currently no treatment to slow or stop Parkinson’s disease. Current medications do not slow the progression of the disease and can only treat certain symptoms. But medications like Levodopa that work early in the disease often become ineffective over the years and require increasing doses, which can lead to disabling side effects. Without understanding the underlying molecular cause of Parkinson’s disease, researchers will be unable to develop a drug that will stop the disease from getting progressively worse in patients.
Many factors, both environmental and genetic, can contribute to the development of Parkinson’s disease. Until recently, the underlying genetic causes of the disease were unknown. Most cases of Parkinson’s are sporadic rather than hereditary, and early studies suggested that a genetic basis was unlikely.
But 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 newly published research, my team and I discovered a new genetic variant linked to Parkinson’s disease, shedding light on the evolutionary origins of various forms of familial parkinsonism, opening the door to better understanding and treating the disease.
Genetic connections and relationships
In the mid-1990s, researchers began investigating whether genetic differences between people with and without Parkinson’s could identify specific genes or genetic variants that cause the disease. Broadly speaking, I and other geneticists use two approaches to map the genetic blueprint of Parkinson’s disease: linkage analysis and association studies.
Linkage analysis focuses on rare families in which parkinsonism or neurological conditions with symptoms similar to Parkinson’s disease are transmitted. This technique looks for cases in which the disease-causing version of the gene and Parkinson’s disease are transmitted in the same person. It requires information about your family tree, clinical data and DNA samples. Relatively small numbers of families (e.g. families with more than two living, affected relatives willing to participate) are needed to accelerate new genetic discoveries.
The “link” between a pathogenic genetic variant and disease development is so important that it can shed light on diagnosis. It also became the basis for many laboratory models used to study the consequences of gene dysfunction and how to correct it. Like the linkage studies my team and I published, pathogenic mutations were detected in more than 20 genes. In particular, many patients in families with parkinsonism 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 Parkinson’s disease in the general population.
Conversely, genome-wide association studies, or GWAS, compare genetic data from Parkinson’s patients to unrelated individuals of the same age, gender, and ethnicity who do not have the disease. Typically this involves assessing how often more than 2 million common gene variants occur in both groups. Because these studies require analyzing so many gene variants, researchers must collect clinical data and DNA samples from more than 100,000 people.
Although expensive and time-consuming, findings from genome-wide association studies are broadly applicable. Combining data from these studies identified several locations in the genome that contribute to the risk of developing Parkinson’s. There are currently more than 92 locations in the genome containing approximately 350 genes potentially involved in the disease. However, GWAS positions can only be evaluated in aggregate; Because these individual genes contribute little to disease risk, individual results are not useful in diagnosis or disease modeling.
Together, the “linked” and “associated” discoveries imply that a number of molecular pathways are involved in Parkinson’s disease. Each identified gene and the proteins they encode can typically have more than one effect. The functions of each gene and protein may also vary depending on the cell type. The question is: Which gene variants, functions and pathways are most relevant to Parkinson’s disease? How will researchers connect this data in a meaningful way?
Parkinson’s disease genes
Using linkage analysis, my team and I identified a novel genetic mutation for Parkinson’s disease called RAB32 Ser71Arg. This mutation was linked to parkinsonism in three families and was found in 13 more 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 containing RAB32 Ser71Arg. This suggests that these patients are all related to the same person; they are distant cousins by descent. It is also suggested that there are many more cousins to be identified.
By further analysis, we found that RAB32 Ser71Arg interacts with several proteins previously associated with early- and late-onset parkinsonism, as well as non-familial Parkinson’s disease. The RAB32 Ser71Arg variant also causes similar dysfunctions in cells.
Together, the proteins encoded by these linked genes optimize levels of the neurotransmitter dopamine. In Parkinson’s disease, dopamine is lost as the cells that produce dopamine gradually die. Together, these linked genes and the proteins they encode regulate specific autophagy processes. In addition, these encoded proteins enable immunity to occur in cells.
Such linked genes support the idea that these causes of hereditary parkinsonism evolved to improve survival in early life because they enhance the immune response against pathogens. Although RAB32 Ser71Arg provides a susceptible genetic background for Parkinson’s in later life, it suggests how and why many mutations arise.
RAB32 Ser71Arg is the researchers’ first linked gene, directly connecting the dots between previous linked discoveries. The encoded proteins bring together three important functions of the cell: autophagy, immunity and mitochondria function. While autophagy releases energy stored in the cell’s garbage dump, this must be coordinated with another specialized component within the cell, the mitochondria, the main energy supplier. Mitochondria also help control cell immunity because they evolved from bacteria, which the cell’s immune system recognizes as “itself” rather than as an invading pathogen that must be destroyed.
Identifying subtle genetic differences
Finding the molecular blueprint of familial Parkinson’s disease is the first step in correcting the faulty mechanisms behind the disease. Like the owner’s manual for your car’s engine, it provides a practical guide to what to check when the engine fails.
Just as each motor pattern is slightly different, what makes each person genetically susceptible to non-familial Parkinson’s disease is also very different. But analysis of genetic data can now test for the types of dysfunction in cells that are hallmarks 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 may help protect against the disease.
More patients and families are needed to participate in genetic research to find additional components of the engine behind Parkinson’s disease. Each person’s genome has approximately 27 million variants of the 6 billion building blocks that make up their genes. Parkinson’s disease has many genetic components that have not yet been found.
As our discovery shows, each new gene researchers identify could significantly improve our ability to predict and prevent Parkinson’s disease.
This article is republished from The Conversation, an independent, nonprofit news organization providing facts and authoritative analysis to help you understand our complex world. Written by Matthew Farrer university of florida
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Matthew Farrer holds US patents relating to LRRK2 mutations and related mouse models (8409809 and 8455243) and methods for treating neurodegenerative disease (20110092565). He has previously received support from the Mayo Foundation, GlaxoSmithKline and NIH (NINDS P50 NS40256; NINDS R21 NS064885; 2005–2009), the Canadian Research Chairs of Excellence program (CIHR/IRSC 275675, 2010–17), the Weston Foundation, and Michael. J Fox Foundation. His work also includes Dr. He is also supported by the Don Rix BC Genetic Medicine Leadership Chair (2011–2019) and most recently the Lee and Lauren Fixel Chair (2019-2024).