Promising Outcomes of Original Grant:
Our original goal was to resolve the role of known LRRK2 coding variants in susceptibility to Parkinson’s disease. Our studies have nominated risk factors for disease in both Asian and Caucasian populations. In addition a common protective haplotype was identified that may reflect a reduction in the toxic function of the LRRK2 protein. These findings support the hypothesis that genetic variation at the LRRK2 locus has a greater role in Parkinson’s disease susceptibility than initially thought.
Objectives for Supplemental Investigation:
Studies to date have shown a strong ethnic-specificity displayed by a number of LRRK2 variants. This was observed in our LRRK2 variant studies with two risk factors nominated with each one specific to either the Asian or Caucasian series but not present in both. This supports the hypothesis that for populations or ethnicities that have not yet been fully sequenced for the LRRK2 gene there is the potential to identify common penetrant mutations and new risk factors for Parkinson’s disease. Studies in these populations will provide a more accurate measure of the global impact of LRRK2 in disease.
Importance of This Research for the Development of a New PD Therapy:
Identifying novel Parkinson’s disease related LRRK2 variants in distinct populations/ethnicities that have yet to be sequenced will provide a greater understanding of the role of LRRK2 variation in Parkinson’s disease on the global stage. With the identification of each new penetrant mutation or risk factor we gain insight into the functional pathomechanisms underlying disease susceptibility. These disease-related variants may themselves be a therapeutic target (e.g. allele-specific knockdown) or may highlight a function of the protein which may be targeted.