Context

In a newly published research, a new genetic variant linked to Parkinson’s disease has been discovered that sheds light on the evolutionary origin of multiple forms of familial parkinsonism.

Newly Discovered Genetic Variant that Causes Parkinson’s Disease Clarifies

• This discovery presents opportunities for better understanding and treatment of the disease.
• Newly Identified Genetic Mutation: Using the linkage analysis, a new genetic mutation has been identified for Parkinson’s disease called RAB32 Ser71Arg. 
• Mutation Linked to Parkinsonism: This mutation was linked to parkinsonism in three families and found in 13 other people in several countries, including Canada, France, Germany, Italy, Poland, Turkey, Tunisia, the U.S. and the U.K.

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• Identical fragment of chromosome 6: The affected individuals and families share an identical fragment of chromosome 6 that contains RAB32 Ser71Arg. 
  • This indicates that these patients share a common ancestor implying that there are likely numerous additional cousins yet to be identified.

Mechanism of New Genetic Variant RAB32 Ser71Arg

• Interactions with Parkinsonism Proteins and Cellular Dysfunction: RAB32 Ser71Arg interacts with several proteins previously linked to early- and late-onset parkinsonism as well as nonfamilial Parkinson’s disease. 
  • The RAB32 Ser71Arg variant also causes similar dysfunction within cells.
• Optimization of Neurotransmitter Dopamine: Together, the proteins encoded by these linked genes optimize levels of the neurotransmitter dopamine. 
  • Dopamine is lost in Parkinson’s as the cells that produce it progressively die. 
  • Together, these linked genes and the proteins they encode regulate specialized autophagy processes.  In addition, these encoded proteins enable immunity within cells.
•  Immune Response Enhancement: Such linked genes support the idea that these causes of inherited parkinsonism evolved to improve survival in early life because they enhance immune response to pathogens.
• Insights into the Origin of Parkinson’s Mutations: RAB32 Ser71Arg suggests how and why many mutations have originated, despite creating a susceptible genetic background for Parkinson’s in later life.
  • RAB32 Ser71Arg marks the first instance where researchers have established a direct connection between prior linked findings in genetic research.
• Coordination of Cell Functions: The proteins encoded bring together three important functions of the cell: autophagy, immunity and mitochondrial function. 
  • While autophagy releases energy stored in the cell’s trash, this needs to be coordinated with mitochondria which serve as the primary energy source.
  • Mitochondria also help to control cell immunity because they evolved from bacteria the cell’s immune system recognizes as “self” rather than as an invading pathogen to destroy.

About Parkinson’s Disease

• About: It is a neurodegenerative movement disorder that progresses relentlessly. It gradually impairs a person’s ability to function until they ultimately become immobile and often develop dementia. 
• Contributing Factors: Many factors may contribute to the development of Parkinson’s, both environmental and genetic. 
• Lack of Adequate Treatment: There is currently no treatment to slow or halt Parkinson’s disease. Available drugs don’t slow disease progression and can treat only certain symptoms. 
  • Medications that work early in the disease generally become ineffective over the years, necessitating increased doses that can lead to disabling side effects. 
  • Thus, there is a need to understand the fundamental molecular cause of Parkinson’s to develop a medication to stop the disease from steadily worsening in patients.

Approaches to Map the Genetic Blueprint of Parkinson’s

• Linkage Analysis: 

  • Targeting Rare Familial Cases with Hereditary Transmission: It focuses on rare families wherein parkinsonism or neurological disorders sharing symptomatic similarities with Parkinson’s are hereditarily transmitted. 
    • This technique looks for cases where a disease-causing version of the gene and Parkinson’s appear to be passed down in the same person. 
  • Criteria for Family-Based Studies: It requires information on your family tree, clinical data and DNA samples. 
    • Relatively few families, such as those with more than two living, affected relatives willing to participate, are needed to expedite new genetic discoveries.
  • Significance: “Linkage” between a pathogenic genetic variant and disease development is so significant that it can inform a diagnosis. 
    • It has also become the basis of many lab models used to study the consequences of gene dysfunction and how to fix it.
    • Linkage studies have identified pathogenic mutations in over 20 genes. 
    • Many patients in families with parkinsonism have symptoms that are indistinguishable from typical, late-onset Parkinson’s. 

• Genome-wide Association Studies(GWAS): 

  • It compares genetic data from patients with Parkinson’s with unrelated people of the same age, gender and ethnicity who don’t have the disease. 
    • Assessing Frequency of Common Gene Variants: This involves assessing how frequently in both groups over 2 million common gene variants appear. 
      • Researchers need to gather clinical data and DNA samples from over 100,000 people because these studies require analyzing so many gene variants.
    • Applicability of GWAS: Combining the data of these studies has identified many locations in the genome that contribute to the risk of developing Parkinson’s. 
    • Aggregate Analysis: Currently, there are over 92 locations in the genome that contain about 350 genes potentially involved in the disease. 
      • However, GWAS locations can be considered only in aggregate and individual results are not helpful in diagnosis nor in disease modeling, as the contribution of these individual genes to disease risk is so minimal.

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Significance of Study

• Detection of Cellular Dysfunctions: The analysis of genetic data can now detect cellular dysfunctions characteristic of Parkinson’s disease.
• Role of Environmental Factors: This will help researchers identify environmental factors that influence the risk of developing Parkinson’s, as well as medications that may help protect against the disease.
• Prediction of Disease: Each new gene that researchers identify can improve our ability to predict and prevent Parkinson’s.