LRRK2 target validation

The implication of LRRK2 as a potential target for neuroprotection strategies in PD clearly originated from human genetic studies. The LRRK2 protein had not been previously identified as a critical mediator of cell-death pathways or mechanisms important in neuron survival before the identification of mutations causative of PD. Further, most individuals with PD do not harbor known LRRK2 mutations, and
missense mutations are relatively rare in accounting for a small percentage of PD in most populations. Model systems that demonstrate an LRRK2-dependent phenotype are necessary to validate LRRK2 as an appropriate potential therapeutic target and to help address whether LRRK2 would serve as a general target for therapy in PD, because most individuals living with PD presumably do not harbor coding mutations in LRRK2. Thus, the question of whether LRRK2 represents a valid target in PD cases without LRRK2 mutations may not be fully answered until safe and effective modifiers of LRRK2 action are available in the clinic.