title: Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson's disease.
abstract: Aging, genetics and environmental toxicity are important etiological factors in Parkinson's disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2R1441G(leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death. Compared with wild-type controls, striatal synaptosomes isolated from young mutant mice exhibited significantly lower dopamine uptake after rotenone toxicity, due to reduced striatal synaptosomal mitochondria and synaptic vesicular proton pump protein (V-ATPase H) levels. Mutant mice developed greater locomotor deficits in open-field tests than wild-type mice following low oral rotenone doses given twice weekly over 50 weeks (half their lifespan). The increased locomotor deficit was associated with specific reduction in striatal mitochondrial Complex-I (NDUFS4) in rotenone-treated mutant but not in similarly treated wild-type mice. Our unique experimental model which incorporates genetic effect, natural aging and prolonged oral environmental toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable and measurable phenotype, is invaluable in further studies of the pathogenic process and therapeutics of 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.
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: Gideon Chi-Ting
authors.initials: GC
authors.lastname: Leung
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong.
authors.forename: Colin Siu-Chi
authors.initials: CS
authors.lastname: Lam
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: Lingfei
authors.initials: L
authors.lastname: Li
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: Institute of Metabolism and Systems Research, University of Birmingham, United Kingdom.
authors.forename: David Boyer
authors.initials: DB
authors.lastname: Ramsden
authors.affiliation: Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong.
authors.forename: Shu-Leong
authors.initials: SL
authors.lastname: Ho
mesh_terms: D000284:Administration, Oral; D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D055879:Gene Knock-In Techniques; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012402:Rotenone / Q000494:pharmacology* / Q000627:therapeutic use; D013574:Synaptosomes / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: C534449:Ndufs4 protein, mouse; D012402:Rotenone; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; D042967:Electron Transport Complex I; D004298:Dopamine