by Parkinson’s disease is a neurodegenerative movement disorder that progresses relentlessly. It gradually affects 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 are affected by Parkinson’s, and both new cases and the total number are steadily increasing.
There is currently no treatment to slow or stop Parkinson’s disease. The available drugs 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, become ineffective over the years, requiring increased doses that can lead to disabling side effects. Without understanding the underlying molecular cause of Parkinson’s, it is unlikely that researchers will be able to develop a medication to stop 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 the disease were unknown. Most cases of Parkinson’s are rarely inherited, and early studies suggested that 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 that sheds light on the evolutionary basis of multiple forms of familial dementia, opening doors to better understanding and treating the disease.
Genetic linkages and associations
In the mid-1990s, researchers began looking at whether genetic differences between people with Parkinson’s disease could identify specific genes or genetic variants that cause the disease. In general, I and other geneticists use two approaches to map the genetic blueprint of Parkinson’s: linkage analysis and association studies.
Linkage analysis focuses on rare families in which parkin decreases, or neurological conditions with symptoms similar to Parkinson’s disease. This technique looks for cases where it appears that a disease-causing version of the gene and Parkinson’s disease are being described in the same person. It requires information about your family tree, clinical data and DNA samples. Few families, such as those with more than two living, affected relatives are willing to participate, to speed up new genetic discoveries.
A “link” between a pathogenic genetic variant and disease development is so significant that it can lead to 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, like the one published by my team and I, have identified pathogenic mutations 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, parkinsonism, which usually affects people with earlier-onset disease, may not be the cause of Parkinson’s in the general population.
Conversely, genome-wide association studies, or GWAS, compare genetic data from patients with Parkinson’s disease to unrelated people of the same age, gender and ethnicity who do not have the disease . Typically, this involves assessing how often in both groups more than 2 million common gene variants appear. Because these studies require the analysis of so many gene variations, researchers must collect clinical data and DNA samples from over 100,000 people.
Although expensive and time-consuming, the results of genome-wide association studies are widely applicable. Combining the data from these studies identified many locations in the genome that increase the risk of developing Parkinson’s disease. Currently, there are over 92 locations in the genome containing approximately 350 genes that may be involved in the disease. However, GWAS loci can only be considered as a whole; individual results do not help with diagnosis or disease modeling, as the contribution of these individual genes to disease risk is small.
Together, these “linked” and “associated” findings suggest that several molecular pathways are involved in Parkinson’s. All known genes and the proteins they encode can usually have more than one effect. The functions of each gene and protein may also vary by cell type. The question is which gene version, functions and pathways are most associated with Parkinson’s? How do researchers connect this data wisely?
Parkinson’s disease genes
Using linkage analysis, my team and I identified a new genetic mutation for Parkinson’s disease called RAB32 Ser71Arg. This mutation has been linked to parkinsonism in three families and has been found in 13 other people in several countries, including Canada, France, Germany, Italy, Poland, Turkey, Tunisia, the US and the UK.
Although the affected individuals and families come from many parts of the world, they share an identical fragment of chromosome 6 containing RAB32 Ser71Arg. This suggests that these patients are all related to the same person; ancestors, they are distant cousins. It also suggests that there are many more cousins to identify.
With further analysis, we found that RAB32 Ser71Arg interacts with several proteins previously linked to early and late 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 autophagic processes. In addition, these encoded proteins enable immunity within cells.
Such linked genes support the idea that these reasons for heritable pitching have improved to survive 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 susceptible to Parkinson’s later in life.
RAB32 Ser71Arg is the first linked gene researchers have identified that directly connects the dots between previous linked discoveries. The encoded proteins bring together three important functions of the cell: autophagy, immunity and mitochondrial function. Although autophagy releases energy stored in the cell’s waste, this must be coordinated with another specialized component within the cell, mitochondria, which are the main supplier of energy. Mitochondria also help regulate cell immunity because they evolved from bacteria that the cell’s immune system recognizes as “self” rather than an invading pathogen to be destroyed.
Recognizing subtle genetic differences
The first step to fixing the faulty mechanisms behind the disease is to find the molecular blueprint for familial Parkinson’s disease. Like the owner’s manual for your car’s engine, it provides practical guidance on what to check when the motor fails.
Just as each motor make-up is slightly different, what makes each person genetically susceptible to non-familial Parkinson’s disease is also slightly different. However, it is now possible to analyze genetic data to test for the types of cell dysfunction 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 participating in genetic research are needed to uncover additional components of the machinery behind Parkinson’s. Each person’s genome contains about 27 million versions of the 6 billion building blocks that make up their genes. There are many more genetic components to Parkinson’s that have not yet been discovered.
As our discovery shows, each new gene that researchers identify can greatly improve our ability to predict and prevent Parkinson’s disease.
This article is republished from The Conversation, a non-profit, independent news organization that brings you reliable facts and analysis to help you make sense of our complex world. It was written by: Matthew Farrer, University of Florida
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Matthew Farrer holds US patents related to LRRK2 mutations and related mouse models (8409809 and 8455243), and methods of 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 Canada Excellence Research Chairs program (CIHR/IRSC 275675, 2010–17), the Weston Foundation Foundation J Fox. The Chair of Leadership supported Dr. Don Rix BC in Genetic Medicine (2011–2019) also for his work and, more recently, from the Lee and Lauren Fixel Chair (2019–2024).
