The homozygous LRRK2.p.N1437D point mutation mouse is a novel model of parkinsonism

The leucine-rich repeat kinase 2 (LRRK2) gene is one of the most common genetic causes of autosomal dominant Parkinson's disease (PD) and a common genetic risk factor for sporadic PD. However, aged mice with common LRRK2 point mutations fail to exhibit age-related PD-associated behavioral and pathological impairments. We generated a novel mouse model harboring the LRRK2.p.N1437D point mutation (c.4309 A > G; NM_98578). Here, the homozygous N1437D mutation, but not the heterozygous mutation, led to an increase in the autophosphorylation, substrate phosphorylation, and GTP-binding capacity of LRRK2. Heterozygous N1437D mice also showed unaffected behavior and pathology while the homozygous mice exhibited PD-associated behavioral change at 25–26 months, dopamine system damage, lipofuscin accumulation, and lipid peroxidation in substantia nigra dopaminergic neurons at 26–27 months. The new N1437D point mutation mouse does not require LRRK2 overexpression and may better mimic the pathological characteristics of LRRK2 mutation in the ROC-COR region.