Lrrk2 Conditional Knockout mouse models

Lrrk2, the mouse ortholog of human LRRK2, encodes a large multidomain protein combining armadillo, ankyrin, and leucine-rich repeats with a ROC GTPase domain, a COR linker, a serine/threonine kinase domain, and a WD40 tail, functioning as a dimeric kinase recruited to damaged or stressed membranes. Its validated substrates are a subset of Rab GTPases, including Rab8a, Rab10, and Rab29, phosphorylated at a conserved threonine in the switch II motif, which blocks GDI binding and reroutes membrane trafficking, ciliogenesis, and lysosomal repair. The G2019S mutation in the kinase domain and R1441C/G in the ROC domain increase Rab10 phosphorylation and cause autosomal dominant Parkinson disease, so knockin alleles, not deletion, reproduce the disease mechanism, while nulls are viable but develop kidney and lung lamellar body pathology that constrains interpretation and mirrors the on-target liability of kinase inhibitors. Kinase-dead knockins separate scaffolding from catalysis; use phospho-Rab10 as the pharmacodynamic endpoint.

Tissue restricted knockout of Lrrk2 keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.