Study Rationale: Genetic variance at the LRRK2 gene locus is associated with risk of Parkinson’s disease (PD). Most evidence suggests that this variation increases the activity of the encoded LRRK2 kinase protein. This observation has led to the proposal that inhibition of LRRK2 kinase activity would be therapeutically beneficial for all PD patients, not just those harboring LRRK2 mutations. However, this approach would only work if there are similar mechanisms underlying both LRRK2-associated PD and PD that is idiopathic—due to unknown causes. This proposal will explore whether LRRK2 dysfunction is responsible for similar pathological features in idiopathic and LRRK2-associated PD.
Hypothesis: We will assess whether LRRK2 kinase activity is elevated in idiopathic PD as well as LRRK2-associated PD, and determine which types of brain cells exhibit this elevated activity.
Study Design: We have assembled a panel of reagents that allow fluorescent imaging of components of the LRRK2 pathway, detection of neurodegeneration markers and identification of cell type. We will use this panel in a technique termed CODEX (co-detection by indexing), which allows us to visualize these multiple markers all at once. By applying CODEX to postmortem brain samples, we will assess LRRK2 activity in the brains of idiopathic and LRRK2-associated PD, and we will determine in which cell types this activity can be detected.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, our CODEX technique will identify a shared mechanism in idiopathic and LRRK2-associated PD. This finding would enhance our confidence in using LRRK2-targeted therapeutics to treat individuals with LRRK2 mutations and those for which the disease etiology is unknown.
Next Steps for Development: This technology could be applied to other brain regions and to a larger number of idiopathic samples to correlate with neuropathological measurements already in use. Should our panel reveal novel pathological signatures in PD, it could be applied broadly as a diagnostic for LRRK2 activity in PD pathology.