Parkinson’s disease is a neurodegenerative movement disorder that progresses relentlessly. It gradually reduces a person’s ability to function until he/she eventually becomes immobile and often develops dementia. In the US alone, well over a million people suffer from Parkinson’s disease, and the number of new cases and the total number are steadily increasing.
There is currently no treatment to slow or stop Parkinson’s disease. Available medications do not slow disease progression and can only treat certain symptoms. However, medications that work early in the disease, such as Levodopa, generally become ineffective over the years, requiring increased doses that can lead to disabling side effects. Without understanding the fundamental molecular cause of Parkinson’s, it is unlikely that researchers can develop a drug to prevent the disease from steadily worsening in patients.
There are many factors that can contribute to the development of Parkinson’s, both environmental and genetic factors. Until recently, the underlying genetic causes of the disease were unknown. Most cases of Parkinson’s are not hereditary but sporadic, and early studies suggested that a genetic basis was unlikely.
Nevertheless, 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 recently published research, my team and I discovered a new genetic variant linked to Parkinson’s that sheds light on the evolutionary origins of multiple forms of familial Parkinsonism, opening doors to better understanding and treating the disease.
Genetic links and associations
In the mid-1990s, researchers began investigating whether genetic differences between people with or without Parkinson’s 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 parkinsonism, or neurological disorders with similar symptoms to Parkinson’s, are passed on. This technique looks for cases where a disease-causing version of the gene and Parkinson’s disease appear to be passed on 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 expedite new genetic discoveries.
The ‘link’ between a pathogenic genetic variant and the development of disease is so important that it can provide a diagnosis. It has also become the basis of many laboratory models used to study the consequences of gene dysfunction and how to correct it. Linkage studies, such as the one my team and I published, have identified pathogenic mutations in more than twenty genes. It is striking that many patients in families with parkinsonism have symptoms that are indistinguishable from the typical, late-onset form of Parkinson’s. Nevertheless, hereditary parkinsonism, which typically affects people with previous 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 with unrelated people of the same age, sex and ethnicity who do not have the disease. Typically, this involves assessing how common more than 2 million common gene variants are 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, the findings from genome-wide association studies are broadly applicable. Combining data from these studies has identified many locations in the genome that contribute to the risk of developing Parkinson’s. Currently, there are more than 92 locations in the genome containing approximately 350 genes that may be involved in the disease. However, GWAS locations can only be considered in aggregate; individual results are not useful in diagnosis, nor in disease modeling, because the contribution of these individual genes to disease risk is so minimal.
Together, ‘linked’ and ‘associated’ discoveries imply that a number of molecular mechanisms are involved in Parkinson’s disease. Each identified gene and the proteins they code for can typically have more than one effect. The functions of each gene and protein can also vary between cell types. The question is which gene variants, functions and pathways are most relevant for Parkinson’s? How do researchers connect this data in a meaningful way?
Genes for Parkinson’s disease
Using linkage analysis, my team and I identified a novel genetic mutation for Parkinson’s disease called RAB32 Ser71Arg. This mutation has been associated with 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 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; ancestrally 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-onset parkinsonism, as well as to non-familial Parkinson’s disease. The RAB32 Ser71Arg variant also causes a similar dysfunction in cells.
Together, the proteins encoded by these linked genes optimize levels of the neurotransmitter dopamine. Dopamine is lost in Parkinson’s because 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 immunity within cells.
Such linked genes support the idea that these causes of hereditary parkinsonism have evolved to improve survival in early life because they enhance the immune response to pathogens. RAB32 Ser71Arg suggests how and why many mutations arose despite creating a susceptible genetic background for Parkinson’s in later life.
RAB32 Ser71Arg is the first linked gene researchers have identified that directly connects the dots between previously linked discoveries. The encoded proteins bring together three important functions of the cell: autophagy, immunity and mitochondrial function. While autophagy releases energy stored in the cell’s waste, this must be coordinated with another specialized component within the cell, the mitochondria, which are the main energy supplier. Mitochondria also help control cell immunity because they arise from bacteria that are recognized by the cell’s immune system as ‘self’ rather than as an invading pathogen that needs to be destroyed.
Identifying subtle genetic differences
Finding the molecular blueprint for familial Parkinson’s is the first step toward solving the faulty mechanisms behind the disease. Like the owner’s manual that comes with your car’s engine, it provides a practical guide on what to check if the engine breaks down.
Just as each brand of motorcycle is subtly different, what makes each person genetically predisposed to non-familial Parkinson’s disease is also subtly different. However, analyzing genetic data can now test for types of cell dysfunction that characterize Parkinson’s disease. This will help researchers identify environmental factors that influence the risk of developing Parkinson’s, as well as medications that can help protect against the disease.
More patients and families are needed to participate in genetic research to find additional components of the driver of Parkinson’s. The genome of every human contains approximately 27 million variants of the 6 billion building blocks that make up genes. There are many more genetic components to Parkinson’s that have yet to be found.
As our discovery illustrates, each new gene that researchers identify can profoundly improve our ability to predict and prevent Parkinson’s disease.
This article is republished from The Conversation, an independent nonprofit organization providing facts and trusted analysis to help you understand 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 associated mouse models (8409809 and 8455243), and methods for treating neurodegenerative diseases (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 and the Michael J Fox Foundation. His work was also supported by the Dr. Don Rix BC Leadership Chair in Genetic Medicine (2011–2019) and most recently as the Lee and Lauren Fixel Chair (2019–2024).