title: 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) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Liu
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong ; Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong Hong Kong.
authors.forename: Song
authors.initials: S
authors.lastname: Lu
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong ; Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong Hong Kong.
authors.forename: Philip Wing-Lok
authors.initials: PW
authors.lastname: Ho
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong.
authors.forename: Ho-Man
authors.initials: HM
authors.lastname: Tse
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong.
authors.forename: Shirley Yin-Yu
authors.initials: SY
authors.lastname: Pang
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong.
authors.forename: Michelle Hiu-Wai
authors.initials: MH
authors.lastname: Kung
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong ; Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong Hong Kong.
authors.forename: Jessica Wing-Man
authors.initials: JW
authors.lastname: Ho
authors.affiliation: Department of Clinical and Experimental Medicine, University of Birmingham Birmingham, United Kingdom.
authors.forename: David B
authors.initials: DB
authors.lastname: Ramsden
authors.affiliation: Department of Biochemistry, University of Hong Kong Hong Kong.
authors.forename: Zhong-Jun
authors.initials: ZJ
authors.lastname: Zhou
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong ; Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong Hong Kong.
authors.forename: Shu-Leong
authors.initials: SL
authors.lastname: Ho