UCSF

Parkinson’s Disease (PD) is a neurodegenerative disorder that has results in progressive loss of motor control, and sometimes dementia in the late stage of the disease. Despite the many treatments on the market for PD patients, none are efficacious in modifying the course of disease progression or overall prognosis. Further advancements in the understanding of PD etiology is necessary to develop more effective treatments. Mutations in LRRK2 are responsible for a plurality of hereditary PD cases, and GWAS studies have implicated LRRK2 in sporadic PD cases as well. Kinase inhibition is seen as a potential therapeutic strategy for PD, and several kinase inhibitors are under clinical investigation. We are developing two separate strategies for targeting the LRRK2 GTPase domain, which exerts regulatory control over the kinase domain via unknown mechanisms. Drugging the LRRK2 GTPase offers a different approach to LRRK2 modulation, and will help elucidate the role of the GTPase domain of LRRK2 in pathogenesis.

The first strategy described is an orthosteric approach, from direct competition against nucleotide binding in the active site. Roc GTPases, of which LRRK2 is a member, have lower affinity for nucleotide than other Ras-like GTPases. This represents a potential window for competition that does not exist for most GTPases. The second strategy employs chemical genetics to target an introduced cysteine and an accompanying set of allosteric switch II pocket chimeric residues, obviating the need to screen for novel chemical matter and enabling studies of LRRK2 GTPase modulation in cell.