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

Hui Fang Liu, Song Lu, Philip Wing Lok Ho, Ho Man Tse, Shirley Yin Yu Pang, Michelle Hiu Wai Kung, Jessica Wing Man Ho, David B. Ramsden, Zhong Jun Zhou, Shu Leong Ho

Research output: Journal article publicationJournal articleAcademic researchpeer-review

36 Citations (Scopus)

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 LRRK2R1441G mutation on nigrostriatal synaptic nerve terminals and locomotor activity, we generated C57BL/6N mice with homozygous LRRK2R1441G knockin (KI) mutation, and examined for early changes in nigrostriatal region, striatal synaptosomal [3H]-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) 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 LRRK2R1441G 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.

Original languageEnglish
Pages (from-to)199-208
Number of pages10
JournalAnnals of Clinical and Translational Neurology
Volume1
Issue number3
DOIs
Publication statusPublished - Mar 2014
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Neurology

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