Dataset Information

LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity.

ABSTRACT:

Objective

Mutations in leucine-rich repeat kinase 2 (LRRK2) pose a significant genetic risk in familial and sporadic Parkinson's disease (PD). R1441 mutation (R1441G/C) in its GTPase domain is found in familial PD. How LRRK2 interacts with synaptic proteins, and its role in dopamine (DA) homeostasis and synaptic vesicle recycling remain unclear.

Methods

To explore the pathogenic effects of LRRK2(R1441G) mutation on nigrostriatal synaptic nerve terminals and locomotor activity, we generated C57BL/6N mice with homozygous LRRK2(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 (VMAT2) expression in striatum, (3) COX IV, LC3B, Beclin-1 expression in midbrain, (4) LRRK2 expression in total cell lysate from whole brain, (5) ?-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 LRRK2(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 LRRK2-associated PD.

SUBMITTER: Liu HF

PROVIDER: S-EPMC4184549 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Publications

LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity.

Liu Hui-Fang HF Lu Song S Ho Philip Wing-Lok PW Tse Ho-Man HM Pang Shirley Yin-Yu SY Kung Michelle Hiu-Wai MH Ho Jessica Wing-Man JW Ramsden David B DB Zhou Zhong-Jun ZJ Ho Shu-Leong SL

Annals of clinical and translational neurology 20140304 3

<h4>Objective</h4>Mutations in leucine-rich repeat kinase 2 (LRRK2) pose a significant genetic risk in familial and sporadic Parkinson's disease (PD). R1441 mutation (R1441G/C) in its GTPase domain is found in familial PD. How LRRK2 interacts with synaptic proteins, and its role in dopamine (DA) homeostasis and synaptic vesicle recycling remain unclear.<h4>Methods</h4>To explore the pathogenic effects of LRRK2(R1441G) mutation on nigrostriatal synaptic nerve terminals and locomotor activity, we ...[more]

PMID: 25356398

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Dataset Information

LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity.

Objective

Methods

Results

Interpretation

Publications

LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity.

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