Study Rationale:
While most cases of Parkinson’s disease have no known genetic cause, a subset of Parkinson’s is caused by mutations in the leucine-rich repeat kinase 2 (LRRK2) gene. It is believed that even those without LRRK2 mutations may be affected by LRRK2 dysfunction. Therefore, potent inhibitors of LRRK2 have been developed and are currently being evaluated in clinical trials. However, it is currently unclear if those inhibitors will treat the underlying pathologies of Parkinson’s. In Parkinson's, the protein alpha-synuclein aggregates into clumps, which are a hallmark of the disease. Tau is a protein that also accumulates in the brains of people with Parkinson’s. In previous studies, we have evaluated the effect of LRRK2 inhibitors to treat alpha-synuclein pathology in Parkinson’s models. In this study, we will evaluate the impact of LRRK2 mutations and inhibitors on tau pathology.
Hypothesis:
This study will test the hypothesis that LRRK2 function is an important modulator of pathological tau protein spread.
Study Design:
Pre-clinical models that develop tau pathology will be used to assess whether the G2019S mutation in LRRK2 changes the burden or spread of tau pathology throughout the brain. A potent LRRK2 inhibitor will be introduced into pre-clinical models with and without a LRRK2 mutation to assess the effect of LRRK2 inhibitors on tau pathology.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If LRRK2 drives tau pathology in a pre-clinical model and we are able to reverse this pathology with LRRK2 inhibitors, we will have begun to establish a rationale for using LRRK2 inhibitors to treat tau pathology.
Next Steps for Development:
Since LRRK2 inhibitors are already in clinical trials for the treatment of Parkinson’s, this and future studies could expand the potential pool of patients who could benefit from this treatment to those with tau pathology and dementia.