The Role of the LRRK2 Gene in Future PD Treatment

Drugs currently in development to treat an inherited form of Parkinson’s disease (PD) may possess the potential to help the wider Parkinson’s population.1 More than one million people in the US have Parkinson’s, but only 3-4% have the familial form associated with a mutation in the LRRK2 gene. New study findings from the University of Pittsburgh School of Medicine and the Medical Center have identified increased LRRK2 activity present in the substantia nigra area of the brains of people with Parkinson’s who do not have the mutation.

Since 2004, scientists have recognized that changes in the activity of the LRRK2 protein have been associated with the hereditary form of Parkinson’s disease. Yet, this new research, suggests that LRRK2 may affect more people with Parkinson’s than previously thought. There is no known cause for the majority of Parkinson’s; as such it is considered idiopathic PD.2

LRRK2, which stands for leucine-rich repeat kinase 2, is a known contributor to the development of PD. Parkinson’s is a neurodegenerative disorder that causes impaired motor function, cognitive, and psychiatric symptoms.2 The gene mutation typically results in increased LRRK2 activity and was thought to cause PD only when mutated. Yet study findings reveal that it may also play a role in developing PD even without the mutation.1

More than a gene mutation

A new method of observing and measuring LRRK2 activity in nerve cells, developed by J. Timothy Greenamyre, M.D., Ph.D. and colleagues, uses fluorescence to more easily identify the protein. Past LRRK2 research has been limited because of the small amounts present in brain cells making detection difficult to evaluate activity. The Pittsburgh team created a “molecular beacon” that can attach to a receptor on the LRRK2 protein causing it to glow when it is active. This enabled researchers to see nerve cells with active LRRK2 in the brain.1

Results published in the journal Science Translational Medicine described studies using rats. They demonstrated that active LRRK2 blocked nerve cells ability to eliminate or clear alpha-synuclein, causing it to build up or clump. When rats received a drug currently in development for the treatment of familial PD, it blocked LRRK2 activity and the build up of alpha synuclein resulting in Lewy bodies.1 Both genetic and environmental components, like oxidative stress and toxins, can influence the development of Parkinson’s.

Other studies evaluated post-mortem human brain tissue donated for Parkinson’s research. The researchers were able to demonstrate an association between the increase in LRRK2 activity with alpha-synuclein aggregation in dopamine neurons generally affected by PD.1,3 The increase and clumping of alpha-synuclein is associated with the development of Lewy bodies present in both PD and Lewy Body dementia.

The findings tie together more information on the genetic and environmental factors that appear to affect the activity of LRRK2 protein in Parkinson’s. This could potentially influence the development of future therapies in treating all forms of Parkinson’s disease.2 Future research on neurodegeneration associated with increased LRRK2 activity is needed to identify reasons for overactivity. Environmental impact could possibly be modified to prevent or delay the onset or severity of PD.

Future drug development

Drugs in development designed to treat a small percentage of PD cases may find a future role in the treatment for all people with Parkinson’s.1 This could result in significant benefits for everyone suffering from PD (as well as drug companies developing this new class of drugs).

Personalized medicine, including immunotherapies, could be enhanced by information gleaned from gene sequencing and improved access to expanded DNA databases, 23andMe, the health and ancestry company, has been carrying out advanced DNA sequencing as well as drug development and has recently joined forces with the pharmaceutical company Glaxo to share information, and further the study of genetics in targeted therapies.4 DNA sequencing in genetic research, along with drug development, may someday be able to target the causes of PD and other diseases.5

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