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Funded Studies

The Role of LRRK2 in Immune Response and Neurodegeneration Caused by Mitochondrial Dysfunction

Study Rationale:
Although mutations (changes) in the LRRK2 gene are more common than changes in other disease-linked genes in people with Parkinson's disease (PD), it remains unclear how the LRRK2 mutations lead to the death of nerve cells. While protein LRRK2 is studied mostly in nerve cells, it is also produced in large amounts in immune cells. We have recently found that immunity plays a large role in neurodegeneration caused by PD-associated genes other than LRRK2. In this study, we aim to determine if protein LRRK2 also participates in inflammation within the nervous system that leads to neurodegeneration.

We hypothesize that LRRK2 plays a role in the immune response and subsequent neurodegeneration caused by dysfunction of mitochondria -- powerhouses of the cell -- in pre-clinical models.

Study Design:
We will cause mitochondrial stress by exercising pre-clinical models to exhaustion or by inducing mutations in mitochondria's own DNA. Such models will receive drugs or genetic treatment that inhibits LRRK2 (slows its activity). We will then determine if the inhibition of LRRK2 affects inflammation and/or neurodegeneration.

Impact on Diagnosis/Treatment of Parkinson's Disease:
We have linked mitochondrial dysfunction to a harmful immune response and neurodegeneration in pre-clinical models. If LRRK2 inhibitors prevent neurodegeneration, this will support clinical trials of LRRK2 inhibitors.

Next Steps for Development:
LRRK2 inhibitors are already being developed for the treatment of Parkinson's disease. The results of this study would help understand how the LRRK2 inhibitors prevent inflammation, thereby making them more useful. This study may also produce new biomarkers -- disease indicators -- to improve treatment.


  • Richard J. Youle, PhD

    Bethesda, MD United States

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