The Role of LRRK2 in the Accumulation and Spread of Tau Protein

Study Rationale:
Although most cases of Parkinson’s disease (PD) have no known genetic cause, a subset is driven by mutations in a gene called LRRK2 (leucine-rich repeat kinase 2). Further, evidence suggests that even individuals without LRRK2 mutations may experience inappropriate activation of the LRRK2 protein. Inhibitors of LRRK2 are being evaluated in clinical trials, but it is unclear whether they will alleviate the underlying pathologies of PD. We previously evaluated the ability of LRRK2 inhibitors to clear alpha-synuclein aggregates in PD models. Here, we will examine whether LRRK2 mutations drive the accumulation of tau protein — and whether inhibitors reverse this pathology.

Hypothesis:
This study will test the hypothesis that LRRK2 activity modulates the pathological spread of tau, which accumulates to form fibrous protein tangles inside brain cells.

Study Design:
Pre-clinical models that develop neurofibrillary protein tangles will be used to assess whether activating mutations in LRRK2 alter the accumulation or spread of tau aggregates throughout the brain. A potent LRRK2 inhibitor will then be introduced into pre-clinical models — including some that feature an LRRK2 mutation and some that do not — to assess whether these inhibitors can alleviate tau pathology.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
If LRRK2 drives the accumulation and spread of tau 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 these compounds to treat disorders that feature tau pathology.

Next Steps for Development:
Because LRRK2 inhibitors are already in clinical trials for the treatment of Parkinson's, our findings could expand the potential treatment cohorts to include individuals with dementia that is caused by a pathological accumulation of tau.