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Objective  Mutations in leucine‐rich repeat kinase 2 ( LRRK 2) pose a significant genetic risk in familial and sporadic Parkinson's disease ( PD ). R1441 mutation (R1441G/C) in its  GTP ase domain is found in familial  PD . How  LRRK 2 interacts with synaptic proteins, and its role in dopamine ( DA ) homeostasis and synaptic vesicle recycling remain unclear.    Methods  To explore the pathogenic effects of  LRRK 2 R1441G  mutation on nigrostriatal synaptic nerve terminals and locomotor activity, we generated C57 BL /6N mice with homozygous  LRRK 2 R1441G  knockin ( KI ) mutation, and examined for early changes in nigrostriatal region, striatal synaptosomal [ 3 H]‐ DA  uptake and locomotor activity after reserpine‐induced  DA  depletion.    Results  Under normal conditions, mutant mice showed no differences, (1) in amount and morphology of nigrostriatal  DA  neurons and neurites, (2) tyrosine hydroxylase ( TH ),  DA  uptake transporter ( DAT ), vesicular monoamine transporter‐2 ( VMAT 2) expression in striatum, (3)  COX IV ,  LC 3B, Beclin‐1 expression in midbrain, (4)  LRRK 2 expression in total cell lysate from whole brain, (5) α‐synuclein, ubiquitin, and tau protein immunostaining in midbrain, (6) locomotor activity, compared to wild‐type controls. However, after a single intraperitoneal reserpine dose, striatal synaptosomes from young 3‐month‐old mutant mice demonstrated significantly lower  DA  uptake with impaired locomotor activity and significantly slower recovery from the effects of reserpine.    Interpretation  Although no abnormal phenotype was observed in mutant  LRRK 2 R1441G  mice, the  KI  mutation increases vulnerability to reserpine‐induced striatal  DA  depletion and perturbed  DA  homeostasis resulting in presynaptic dysfunction and locomotor deficits with impaired recovery from reserpine. This subtle nigrostriatal synaptic vulnerability may reflect one of the earliest pathogenic processes in  LRRK 2‐associated  PD .

LRRK 2 R1441G mice are more liable to dopamine depletion and locomotor inactivity