Open AccessLRRK 2 R1441G mice are more liable to dopamine depletion and locomotor inactivity
Author(s) -
Liu HuiFang,
Lu Song,
Ho Philip WingLok,
Tse HoMan,
Pang Shirley YinYu,
Kung Michelle HiuWai,
Ho Jessica WingMan,
Ramsden David B.,
Zhou ZhongJun,
Ho ShuLeong
Publication year - 2014
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.45
Subject(s) - lrrk2 , vesicular monoamine transporter 2 , reserpine , striatum , dopamine , tyrosine hydroxylase , vesicular monoamine transporter , medicine , endocrinology , monoamine neurotransmitter , dopamine transporter , neurodegeneration , biology , parkinson's disease , dopaminergic , serotonin , receptor , disease
Abstract 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 .