biostudies-literatureGan LHChina Postdoctoral Science FoundationNational Natural Science Foundation of China (National Science Foundation of China)61https://www.ebi.ac.uk/biostudies/studies/S-EPMC11953335biostudies-literatureUnknown11(1)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 accuNPJ Parkinson's diseaseThe homozygous LRRK2.p.N1437D point mutation mouse is a novel model of parkinsonism.PMC119533352022M710742922493028237126182201406821714218227151182371432Qi ZYTang YLYu WBZhou XYGan LHLiu FTSun YMXiao BGWang JWu JJfalseThe 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 accu2025-01-01T00:00:00Z2025 Mar2025-06-25T03:04:29.227Z2025-06-25T03:04:29.227ZS-EPMC119533354015563210.1038/s41531-025-00905-4