LRRK2 Genetics Therapy and Unintended Consequences

A lot of excitement has been generated in the Parkinson’s disease (PD) scientific community about the LRRK2 gene. While several genes are linked to developing PD, a LRRK2 gene mutation is one of the most common forms of genetic Parkinson’s. In fact, there are several pharmaceutical companies currently looking to find ways to prevent LRRK2 activation as a potential PD treatment. 

However, is it wise to completely disable the LRRK2 gene? What if this gene plays an important role in other important functions? For example, mutations in the LRRK2 gene have been associated with an increased sensitivity to bacterial infections, as well as other immune-related disorders, such as inflammatory bowel disease. 

Further, dysfunction in the mitochondria (the powerhouse of the cell) in the LRRK2 gene has also been linked to PD. Indeed, keeping mitochondria stable and healthy is essential for providing life-saving energy to dopamine-producing cells. Which begs the question, what if the LRRK2 gene is also involved in how well our immune system works? 

Catherine Weindel, a Parkinson’s Foundation postdoctoral fellow, recently published a LRRK2 study in the journal eLife, titled, “LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis” (Weindel et al., 2020). The study investigated whether developing drugs that shut down LRRK2 might unintentionally negatively impact a person’s ability to fight infection. 

Researchers infected normal mice with mycobacterium tuberculosis – the bacterium that causes tuberculosis (TB). As a control, they also infected mice that had the LRRK2 gene removed (known as knockout mice) with TB. Next, they compared the two mice groups’ immune system reactions. They did this by measuring a signaling protein (known as a type I interferon) that is triggered when a cell is infected with a virus to let the immune system know it’s in trouble. 

Results

Many sophisticated tests ranging from gene expression, RNA-sequence analyses, death receptor signaling, to qualitative and quantitative assessments were conducted. The key findings are as follows:  

  • Mice with no LRRK2 gene infected with TB produced the type I interferon – alerting the immune system that an attack was commencing. 
  • Mice with no LRRK2 gene not infected with TB produced the type I interferon – meaning it alerted the immune system to mount an attack, when no attack was happening. 
  • Mice with no LRRK2 gene experienced far more severe TB symptoms that than the mice with a functioning LRRK2 gene.
  • Normal LRRK2 mice infected with TB produced the appropriate response of the type I interferon, and when not infected with TB, appropriately, did not produce the type I interferon. 

What Does It Mean?

The LRRK2 gene produces a protein that is essential for maintaining healthy, stable mitochondria. Mitochondria play a crucial role in generating the energy required for brain cells (including dopamine producing cells) to survive and to do their job. 

This mouse study suggests that mutated LRRK2 genes may impair the immune responses in the brain to such an extent, it triggers the immune system to attack, even when no harm is happening. Thus, this study findings suggests that great care must be taken when creating drugs or therapies that inactivate the LRRK2 gene, as doing so may have unintended negative effects, such as triggering a chronic high alert immune response and diminishing a person’s ability to fight infection.

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about LRRK2 research by vising the below Parkinson’s Foundation recourses or by calling our free Helpline at 1-800-4PD-INFO (473-4636) for answers to all your Parkinson’s questions.

References

Blanca Ramirez, M., Madero-Perez, J., Rivero-Rios, P., Martinez-Salvador, M., Lara Ordonez, A. J., Fernandez, B., . . . Hilfiker, S. (2017). LRRK2 and Parkinson's Disease: From Lack of Structure to Gain of Function. Curr Protein Pept Sci, 18(7), 677-686. doi:10.2174/1389203717666160311121748

Weindel, C. G., Bell, S. L., Vail, K. J., West, K. O., Patrick, K. L., & Watson, R. O. (2020). LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis. Elife, 9. doi:10.7554/eLife.51071

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